Alternative titles; symbols
HGNC Approved Gene Symbol: TP63
SNOMEDCT: 55821006, 720464003, 721972001, 7731005;
Cytogenetic location: 3q28 Genomic coordinates (GRCh38) : 3:189,596,746-189,897,276 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q28 | ADULT syndrome | 103285 | Autosomal dominant | 3 |
| Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 | 604292 | Autosomal dominant | 3 | |
| Hay-Wells syndrome | 106260 | Autosomal dominant | 3 | |
| Limb-mammary syndrome | 603543 | Autosomal dominant | 3 | |
| Orofacial cleft 8 | 618149 | 3 | ||
| Premature ovarian failure 21 | 620311 | Autosomal dominant | 3 | |
| Rapp-Hodgkin syndrome | 129400 | Autosomal dominant | 3 | |
| Split-hand/foot malformation 4 | 605289 | Autosomal dominant | 3 |
Yang et al. (1998) described the cloning of tumor protein p63, which shows strong homology to the tumor suppressor p53 (191170) and the p53-related protein p73 (601990). p63 was detected in a variety of human and mouse tissues, including proliferating basal cells of epithelial layers in the epidermis, cervix, urothelium, and prostate. The p63 gene encodes multiple isotypes with remarkably divergent abilities to transactivate p53 reporter genes and induce apoptosis. The predominant p63 isoforms in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53. The full-length p63 protein contains 448 amino acids. Isoforms of p63 are due to alternative promoters in exons 1 or 3 and alternative splicing of exons at the 3-prime end. These truncated p63 variants can act as dominant-negative agents toward transactivation by p53 and p63. Yang et al. (1998) suggested the possibility of physiologic interactions among members of the p53 family.
Augustin et al. (1998) also cloned a cDNA, which they termed KET, that is related to the tumor suppressor p53. They stated that the 4,846-bp KET cDNA encodes a protein of 680 amino acids that shares 98% identity with the rat homolog. The remarkable degree of conservation lent support to the notion that KET proteins have important basic functions in development and differentiation.
Di Iorio et al. (2005) stated that the p63 gene generates 6 isoforms. The transactivating isoforms are generated by the activity of an upstream promoter, and the N-terminally truncated (delta-N) isoforms, which lack the transactivation domain, are produced from a downstream intronic promoter. For both transcripts, alternative splicing gives rise to 3 different C termini, designated alpha, beta, and gamma.
Deutsch et al. (2011) stated that full-length TAp63-alpha contains an N-terminal transactivation domain, followed by a DNA-binding domain, an oligomerization domain, a sterile-alpha motif (SAM) domain, and a C-terminal transactivation inhibitory (TI) domain.
Yang et al. (1998) determined that the TP63 gene contains 15 exons.
By fluorescence in situ hybridization, Yang et al. (1998) localized the human TP63 gene to chromosome 3q27-q29. Using linkage analysis, they mapped the mouse gene to chromosome 16 in a region known to be syntenic with human 3q27-q29.
By radiation hybrid analysis, Augustin et al. (1998) mapped the TP63 gene to human chromosome 3q27. KET (TP63) is located between the somatostatin gene (SST; 182450) proximally and the apolipoprotein D gene (APOD; 107740) distally. By means of an interspecific backcross panel, Augustin et al. (1998) mapped the murine homolog, Ket, to chromosome 16 in a region that is deleted in early stages of tumorigenesis of mouse islet cell carcinomas and contains the Loh2 gene, a putative suppressor of angiogenesis. Augustin et al. (1998) inferred from mapping data that KET may act as a tumor suppressor and should be considered a candidate for Loh2.
Hibi et al. (2000) stated that p53 (191170) homologs known variously as p40, p51, p63, and p73L (Trink et al., 1998, Yang et al., 1998, Osada et al., 1998, Senoo et al., 1998) are isoforms of the same gene, which Hibi et al. (2000) referred to as AIS for 'amplified in squamous cell carcinoma.' The main difference between the various transcripts is the presence or absence of the N-terminal transcriptional activation domain; p40, delta-Np63, and p73L lack this domain. Though no evidence of a tumor suppressor function was found, Hibi et al. (2000) observed overexpression of this gene in head and neck cancer cell lines and primary lung cancers associated with a low increase of its copy number. Amplification of the AIS locus was accompanied by RNA and protein overexpression of a variant p68(AIS) lacking the terminal transactivation domain. Protein overexpression in primary lung tumors was limited to squamous cell carcinoma and tumors known to harbor a high frequency of p53 mutations. Overexpression of p40(AIS) in Rat 1a cells led to an increase in soft agar growth and tumor size in mice. Results were interpreted as indicating that AIS transcripts lacking the N-terminal transcriptional activation domain play an oncogenic rather than a suppressive role in certain cancers.
Flores et al. (2002) explored the role of p63 and p73 in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for 1 or a combination of these p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene. While using the E1A system facilitated the performance of biochemical analyses, the authors also examined the functions of p63 and p73 using an in vivo system in which apoptosis had been shown to be dependent on p53. Using both systems, Flores et al. (2002) demonstrated that the combined loss of p63 and p73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage. Note that an Expression of Concern was published for the article by Flores et al. (2002).
Benard et al. (2003) suggested that the 2 homologs of TP53, TP73 and TP63, must not have a typical tumor suppressor gene role in human cancers, given the lack of demonstrated mutations in either of these 2 genes. Nevertheless, TP73 and TP63 seem strongly involved in malignancy acquisition and maintenance.
Using DNA microarray analysis with transfected human SAOS2 osteosarcoma cells, Wu et al. (2003) found that both delta-Np63-alpha and TAp63-alpha could activate gene transcription. A comparison of gene profiles revealed that these p63 isoforms influenced a wide variety of partly overlapping targets involved in cell cycle control, stress, and signal transduction. Delta-Np63-alpha and TAp63-alpha often influenced expression of specific genes in an opposite manner.
Di Iorio et al. (2005) found that, depending on the conditions, limbal and corneal keratinocytes may contain all 3 delta-N isoforms of p63. In the uninjured surface of the eye, delta-N p63-alpha was present in the limbus but was absent from the corneal epithelium. Delta-N p63-beta and delta-N p63-gamma appeared upon wounding, and their expression correlated with limbal cell migration and corneal regeneration and differentiation. Di Iorio et al. (2005) concluded that the alpha isoform is necessary for maintenance of the proliferative potential of limbal stem cells and their ability to migrate over the cornea. The beta and gamma isoforms, being suprabasal and virtually absent from the resting limbus, likely play a role in epithelial differentiation during corneal regeneration.
Suh et al. (2006) showed that p63, and specifically the TAp63 isoform, is constitutively expressed in female germ cells during meiotic arrest and is essential in a process of DNA damage-induced oocyte death not involving p53. They also showed that DNA damage induced both the phosphorylation of p63 and its binding to p53 cognate DNA sites and that these events are linked to oocyte death. Suh et al. (2006) concluded that their data supported a model whereby p63 is the primordial member of the p53 family and acts in a conserved process of monitoring the integrity of the female germline, whereas the functions of p53 are restricted to vertebrate somatic cells for tumor suppression.
Yi et al. (2008) showed that miR203 (611899) is induced in the skin concomitantly with stratification and differentiation. By altering miR203's spatiotemporal expression in vivo, they showed that miR203 promotes epidermal differentiation by restricting proliferative potential and inducing cell cycle exit. Yi et al. (2008) identified p63 as one of the conserved targets of miR203 across vertebrates. Notably, p63 is an essential regulator of stem cell maintenance in stratified epithelial tissues. Yi et al. (2008) showed that miR203 directly represses the expression of p63; it fails to switch off suprabasally when either Dicer1 (606241) or miR203 is absent and it becomes repressed basally when miR203 is prematurely expressed. The authors concluded that miR203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighboring layers.
Su et al. (2010) showed that TAp63 suppresses tumorigenesis and metastasis, and coordinately regulates Dicer (606241) and miR130b (613682) to suppress metastasis. Metastatic mouse and human tumors deficient in TAp63 express Dicer at very low levels, and Su et al. (2010) found that modulation of expression of Dicer and miR130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. Su et al. (2010) concluded that their data provided a novel understanding of the roles of TAp63 in tumor and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR130b, and may have implications for the many processes regulated by miRNAs.
Using RNA interference screening to identify targets of p63 in human keratinocytes, Borrelli et al. (2010) showed that HBP1 (616714) was directly repressed by p63. Mice lacking p63 showed increased Hbp1 expression in keratinocytes. HBP1 was activated upon human keratinocyte differentiation and was required for keratinocyte stratification. Borrelli et al. (2010) concluded that suppression of HBP1 enables p63-mediated growth promotion in the lower layers of epidermis and that HBP1 coordinates expression of genes involved in stratification, leading to formation of the skin barrier.
Deutsch et al. (2011) found that TAp63-alpha was maintained in a closed dimeric and inactive conformation in nonstressed murine oocytes. Phosphorylation opened the dimer and permitted formation of the active tetramer from 2 activated dimers. Dephosphorylation did not affect the oligomerization equilibrium. Mutation analysis showed that a helix within the oligomerization domain of TAp63-alpha was crucial for tetramer stabilization and essentially made the activation process irreversible.
By Western blot analysis of transfected 5637 human bladder cancer cells, Scheel et al. (2009) found that expression of a plasmid containing tandem sequences of all 4 MIR302 family members (see MIR302A; 614596) and MIR367 (614600) downregulated p63 expression. Mutation analysis identified 2 functional MIR302 binding sites in the 3-prime UTR of the p63 transcript. Western blot analysis showed that transfection of GH testicular cancer cells with antagonizing oligonucleotides that blocked all MIR302 subspecies resulted in elevated p63 protein levels. RT-PCR confirmed that synthetic MIR302B (614597) downregulated p63 mRNA expression.
Conforti et al. (2013) identified the human E3 ubiquitin ligase PIR2 (RNF144B; 618869) as a direct transcriptional target of p63 and found that PIR2 expression in keratinocytes and squamous cell carcinomas was predominantly dependent on p63. PIR2 depletion impaired proliferation of human epidermal keratinocytes. The authors found that PIR2 functioned downstream of p63 to regulate cell proliferation by mediating p21 (CDKN1A; 116899) degradation. PIR2 depletion also impaired keratinocyte differentiation, as PIR2 expression was required for termination of differentiation in keratinocytes. Moreover, PIR2 depletion increased p63 protein level in keratinocytes, as p63 regulated its own protein level by transcriptionally activating PIR2, leading to p63 proteasomal degradation.
Using mouse knockout models and transfected human cell lines, Restelli et al. (2014) found that DLX5 (600028) and TP63, which both can cause split hand/foot malformations when mutated, are involved in a regulatory loop during limb development. Proteasome-mediated degradation of delta-N p63-alpha was induced by the cis/trans isomerase PIN1 (601052). FGF8 (600483), a downstream DLX5 effector, countered delta-N p63-alpha degradation. Restelli et al. (2014) noted that both the Tp63 and Dlx5/Dlx6 (600030) mouse models of split hand/foot malformations show reduced Fgf8 expression in the apical ectodermal ridge.
In mice, Zuo et al. (2015) showed that preexisting, intrinsically committed distal airway stem cells expressing TRP63 and keratin-5 (KRT5; 148040), called DASC(p63/Krt5), undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. Zuo et al. (2015) also showed that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to prefibrotic lesions and deficient oxygen exchange. Finally, the authors demonstrated that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. Zuo et al. (2015) concluded that the ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.
Vaughan et al. (2015) independently defined the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells that are present within normal distal lung. The authors stated that quiescent LNEPs activate a delta-Np63 (a p63 splice variant) and cytokeratin-5 (Krt5) remodeling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch (190198) signaling to activate the delta-Np63 and cytokeratin-5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signaling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signaling. Vaughan et al. (2015) concluded that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and that the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signaling.
The delta-N isoforms (lacking the acidic transactivation domain) of p63 and p73 (601990) are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53 (191170), p63 bearing the acidic transactivation domain (TAp63), and TAp73 to inhibit their tumor-suppressive functions. Venkatanarayan et al. (2015) showed that deletion of the delta-N isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumors through upregulation of IAPP (147940), the gene that encodes amylin, a 37-amino-acid peptide cosecreted with insulin by the beta cells of the pancreas. Venkatanarayan et al. (2015) found that IAPP is causally involved in tumor regression and that amylin functions through the calcitonin receptor (CALCR; 114131) and RAMP3 (605155) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analog of amylin that is used to treat type 1 and type 2 diabetes, caused rapid tumor regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.
Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome 3
Celli et al. (1999) mapped EEC3 (604292), an autosomal dominant disorder characterized by ectrodactyly, ectodermal dysplasia, and facial clefts, to a region of 3q27 where an EEC-like disorder, limb-mammary syndrome (LMS; 603543), had been mapped. Analysis of the p63 gene, which is located in the critical LMS/EEC3 interval, revealed heterozygous mutations in 9 unrelated EEC3 families. (see, e.g., 603273.0001-603273.0004). Eight mutations resulted in amino acid substitutions that were predicted to abolish the DNA binding capacity of p63; the ninth was a frameshift mutation. Six of the 9 mutations were C-to-T transversions at CpG dinucleotides. Transactivation studies with these mutant p63 isotypes provided a molecular explanation for the dominant character of p63 mutations in EEC3.
Split-Hand/Foot Malformation 4
To assess the potential of p63 as a candidate gene for split-hand/foot malformation (SHFM4; 605289), Ianakiev et al. (2000) analyzed the p63 gene in 2 multigenerational families with SHFM in which segregation analysis had excluded linkage to all previously identified autosomal regions. Two missense mutations, 724A-G in exon 5, which predicted a lys194-to-glu substitution (603273.0005), and 982T-C in exon 7, which predicted an arg280-to-cys substitution (603273.0006). Ianakiev et al. (2000) also identified mutations in the TP63 gene in families with EEC3; see 603273.0007 and 603273.0008.
Ankyloblepharon-Ectodermal Defects-Clefting (AEC) Syndrome
Hay-Wells syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC; 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon, and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia syndromes, including ectrodactyly-ectodermal dysplasia-cleft lip/palate (EEC; 604292), limb-mammary syndrome (LMS; 603543), acro-dermato-ungual-lacrimal-tooth syndrome (ADULT; 103285), and recessive cleft lip/palate-ectodermal dysplasia (CLPED1; 225060). McGrath et al. (2001) analyzed the p63 gene in AEC syndrome patients and identified missense mutations in 8 families (see, e.g., 603273.0009-603273.0010).
In a patient who displayed an overlapping phenotype with features of both AEC and Rapp-Hodgkin syndrome (RHS; 129400), Prontera et al. (2008) identified heterozygosity for an 11-bp duplication in the TP63 gene (603273.0027).
Rinne et al. (2009) analyzed the TP63 gene in 24 individuals from 12 different AEC families, and identified mutations in 21 of those tested; the 3 individuals without an identified mutation included 2 unaffected relatives and 1 patient with a phenotype slightly different than AEC/RHS. Of the 11 different mutations identified, 8 were within the coding region of the sterile alpha motif (SAM) domain, and 3 were located in the exon 14 sequence encoding the transactivation inhibitory (TI) domain.
Using luciferase reporter assays, Beaudry et al. (2009) demonstrated compromise of PERP (609301) induction with some (see 603273.0009) but not all AEC-patient derived TP63 mutants. Skin biopsy analysis of AEC patients revealed a subset displaying aberrant PERP expression, suggesting that PERP dysregulation might be involved in the pathogenesis of this disease. Beaudry et al. (2009) concluded that distinct AEC TP63 mutants could differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients.
Using humanized mouse cDNAs expressed in regenerated human epidermal tissue and keratinocytes in culture, Zarnegar et al. (2012) found that AEC-related mutations within the SAM domain of Tp63 repressed expression of transcriptional activators and markers of epidermal differentiation compared with wildtype Tp63. AEC-mutant Tp63 did not induce apoptosis or alter keratinocyte proliferation. ZNF750 (610226), KLF4 (602253), and GRHL3 (608317) were among a group of epidermal genes significantly downregulated by AEC-related mutations. Chromatin immunoprecipitation analysis and sequencing showed that both wildtype and AEC-mutant Tp63 bound 2 canonical TP63-binding sites near the ZNF750 transcriptional start site. Expression of exogenous ZNF750 in AEC model tissue rescued expression of the majority of TP63 target genes. Introduction of Tp63 variants lacking the SAM domain did not alter expression of epidermal differentiation markers.
By determining the NMR structure of the p63 SAM domain with the AEC-associated mutation L514F, followed by funtional analyses with L514F and other AEC-associated mutations, Russo et al. (2018) showed that AEC mutations destabilized the SAM domain, leading to aggregation of the p63 protein. Moreover, AEC-associated p63 mutants not only caused aggregation of wildtype p63, but they also selectively bound other p53 family members and caused their aggregation. In vitro analysis and in vivo analysis of a mouse AEC model revealed that p63 aggregation impaired both the transactivation and repression functions of p63, as aggregated p63 mutant proteins had weakened ability to bind DNA. Reducing the aggregation propensity of AEC-associated mutant p63 proteins restored their transcriptional activity.
ADULT Syndrome
Amiel et al. (2001) reported a missense mutation (603273.0011) in the TP63 gene in an isolated case of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (103285), which maps to chromosome 3q27. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome. Amiel et al. (2001) considered incomplete penetrance as the most likely explanation.
In affected members of a 2-generation family with ADULT syndrome, Duijf et al. (2002) identified a heterozygous mutation in the TP63 gene (R298Q; 603273.0014). Rinne et al. (2006) identified the R298Q mutation in affected members of 2 unrelated families with ADULT syndrome; 1 was Italian, and the other was Dutch. A third family of Finnish origin had a different mutation at the same codon (R298G; 603273.0022).
In a Dutch mother and daughter with minimal manifestations of ADULT syndrome, including hypothelia and palmar hyperlinearity, van Zelst-Stams and van Steensel (2009) identified heterozygosity for a missense mutation in the C-terminal end of the proline-rich domain of TP63 (P127L; 603273.0026). The authors stated that mutations in this domain have primarily been reported to cause limb-mammary syndrome.
In a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular dysplasia, who did not have the skin and limb manifestations of ADULT syndrome, Valenzise et al. (2008) identified the R298Q mutation in the TP63 gene. The mutation was also found in his mother, who displayed only hypodontia and athelia. Valenzise et al. (2008) noted that their findings highlighted the clinical overlapping of TP63-related ectodermal dysplasias and the difficulty of establishing unequivocal genotype-phenotype correlations.
Limb-Mammary Syndrome
In 2 unrelated patients with limb-mammary syndrome (LMS; 603543), van Bokhoven et al. (2001) sequenced the TP63 gene and identified heterozygosity for 2 different frameshift mutations: a 2-bp deletion in exon 13 (603273.0012) and a 2-bp deletion in exon 14 (603273.0013).
In affected members of a Danish family with features of LMS but without limb anomalies, Mathorne et al. (2020) identified heterozygosity for a nonsense mutation in the TP63 gene (R643X; 603273.0035).
Rapp-Hodgkin Syndrome
In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; 129400), Kantaputra et al. (2003) identified heterozygosity for a missense mutation (S545P; 603273.0019) in the TP73L gene. Kantaputra et al. (2003) stated that this was the first genetic abnormality to be described in RHS, and noted that this provides molecular data to support the clinically observed overlap between EEC, AEC, and RHS.
In a mother and daughter with RHS associated with corneal dystrophy and premature menopause, Holder-Espinasse et al. (2007) identified heterozygosity for a 1-bp deletion in the TP73L gene (603273.0025).
In a patient who displayed an overlapping phenotype with features of both AEC and RHS, Prontera et al. (2008) identified heterozygosity for an 11-bp duplication in the TP63 gene (603273.0027).
Orofacial Cleft 8
Because mutations in the TP63 gene underlie several monogenic malformation syndromes manifesting cleft lip with or without cleft palate, Leoyklang et al. (2006) performed mutation analysis of the 16 exons of the gene in 100 Thai patients with nonsyndromic CL/P (OFC8; 618149). In total, 21 single nucleotide changes were found, of which 6 were in the coding regions, including 3 novel nonsynonymous changes: S90L, R313G (603273.0021), and D564H. The R313G change was concluded to be pathogenic on the basis of its amino acid change, evolutionary conservation, occurrence in a functionally important domain, predicted damaging function, de novo occurrence, and its absence in 500 control individuals. The finding highlighted further the wide phenotypic spectrum of TP63 gene mutations.
In a family (CLP-1055) in which the proband and his father had orofacial cleft-8, Basha et al. (2018) identified heterozygosity for a 2-bp duplication (603273.0029) in the TP63 gene. The mutation, which was found by exome sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. Neither patient had any symptoms of other TP63 disorders.
Premature Ovarian Failure 21
In 2 unrelated women with isolated primary amenorrhea (POF21; 620311) who were negative for mutation in known POF-associated genes, Tucker et al. (2019) identified heterozygosity for 2 different nonsense mutations in the last exon (exon 14) of the TP63 gene, R594X (603273.0030) and W598X (603273.0031). In the family for which parental DNA was available, the mutation was shown to have arisen de novo; neither mutation was found in public variant databases.
In 3 unrelated women with premature ovarian failure, Tucker et al. (2022) identified heterozygosity for missense mutations in the TP63 gene, including R97P (603273.0032) and R647C (603273.0033), which were shown to disrupt TP63 dimerization, causing an open active tetramer conformation with a significant increase in transcriptional activity. The third variant, Y18C, had no detectable impact on conformation or transcriptional activity. Tucker et al. (2022) suggested that POF-related variants cause constitutive activation of the oocyte-specific TAp63-alpha isoform, increasing expression of downstream targets that can initiate the apoptotic pathway in oocytes.
Huang et al. (2023) analyzed WES data from a cohort of 1,030 Chinese women diagnosed with premature ovarian insufficiency, and identified 8 unrelated Chinese women with heterozygous mutations in the TP63 gene, including 3 with secondary amenorrhea and the previously reported R647C mutation, and 1 with primary amenorrhea and the R594X mutation. All but 1 of the mutations were in exon 14; patient 4, who had primary amenorrhea, was heterozygous for a 1-bp deletion in exon 13 (603273.0034). The mutations were confirmed by Sanger sequencing and were either not found or were present at low minor allele frequency in the ExAC and/or gnomAD databases. Functional analysis suggested that variants affecting the C-terminal transactivation-inhibitory domain disrupt the inactive TP63 conformation, generating constitutively active TAp63-alpha that increases expression of target genes and induces apoptosis, thus causing exhaustion of oocytes that results in premature ovarian failure.
Functional Effects of p63 Mutations
Using mouse models, Lo Iacono et al. (2008) found that p63 mutations associated with split-hand/foot malformation (e.g., K194E; 603273.0005) and ectrodactyly-ectodermal dysplasia-cleft lip (e.g., R279H; 603273.0007), which lie within the DNA-binding domain of p63, reduced the ability of p63 to activate DLX5 (600028) and DLX6 (600030) promoter reporter constructs.
Associations Pending Confirmation
For discussion of a possible association between variation in the TP63 gene and lung cancer, see 614210.
For discussion of a possible association between homozygosity or heterozygosity for a rare TP63 insertion polymorphism (rs34201045) and SHFM caused by mutation in the WNT10B gene (601906), see SHFM6 (225300).
Ianakiev et al. (2000) identified 4 TP63 mutations in patients with SHFM4 and EEC3. All 4 mutations were found in exons that fall within the DNA-binding domain of p63. The 2 amino acids mutated in the families with SHFM appeared to be involved primarily in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with DNA.
McGrath et al. (2001) noted that p63 mutations resulting in the AEC syndrome result in amino acid substitutions in the sterile alpha motif (SAM) domain and are predicted to affect protein-protein interactions. In contrast, the vast majority of the mutations found in EEC syndrome are amino acid substitutions in the DNA-binding domain. The authors suggested that a distinct genotype-phenotype correlation can be recognized for EEC and AEC syndromes.
Van Bokhoven and Brunner (2002) reviewed the spectrum of p63 mutations underlying 5 human malformation syndromes. Clustering of mutations established a clear genotype-phenotype correlation: in the DNA binding domain (DBD) for EEC syndrome and in the SAM domain for AEC syndrome. Limb-mammary syndrome (LMS; 603543) differs from EEC syndrome in at least 3 respects: (1) mammary gland and nipple hypoplasia are consistent features of LMS but are only occasionally seen in EEC syndrome; (2) patients with LMS do not have the hair and skin defects that are seen in EEC syndrome; (3) whereas patients with LMS have cleft palate, those with EEC syndrome have cleft lip/palate but never have cleft palate only. Phenotypically, LMS is most similar to ADULT syndrome. Two isolated patients with an LMS phenotype had, in exons 13 and 14, frameshift mutations that resulted in truncation of the p63-alpha protein. Therefore, the abundant p63 product in epithelial cells would be missing the transactivation inhibitory domain (TID).
Brunner et al. (2002) reviewed p63 mutations causing developmental syndromes. They stated that the pattern of heterozygous mutations is distinct for each syndrome, and that consistent with this syndrome-specific mutation pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function.
Rinne et al. (2006) reviewed the clinical features of 227 patients with p63 mutations and detailed the variable phenotypic features associated with 5 mutation hotspots, which are all C-T transitions at CpG islands (see 603273.0001; 603273.0006-603273.0008; 603273.0024).
In affected members of 2 unrelated families with EEC syndrome, features of LMS, and severe micturition difficulties, Maclean et al. (2007) identified the R227Q mutation in the TP73L gene (603273.0024). The authors stated that 4 of the 6 cases/families reported with EEC and the R227Q mutation have manifested this distinct urologic abnormality (see van Bokhoven et al., 2001), indicative of a genotype/phenotype correlation.
Yang et al. (1999) generated mice deficient in p63 by targeted disruption. p63 -/- mice have major defects in their limb, craniofacial, and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches, and epidermal appendages, which are all sites of reciprocal signaling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge (AER), which is essential for limb development. The embryonic epidermis of p63 -/- mice undergoes an unusual process of nonregenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrimal, and salivary glands. Yang et al. (1999) concluded that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.
Mills et al. (1999) independently generated mice deficient in p63. The p63-deficient mice were born alive but had striking developmental defects. Their limbs were absent or truncated, defects that were caused by a failure of the AER to differentiate. The skin of p63-deficient mice did not progress past an early developmental stage: it lacked stratification and did not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth, and mammary glands, were absent in p63-deficient mice.
Keyes et al. (2006) studied spontaneous tumorigenesis in p63 +/- mice in both wildtype and p53-compromised backgrounds. p63 +/- mice were not tumor prone, and mice heterozygous for both p63 and p53 had fewer tumors than p53 +/- mice. The rare tumors that developed in mice with compromised p63 were distinct from those of p53 +/- mice. Furthermore, p63 +/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas. Keyes et al. (2006) concluded that p63 plays a markedly different role in tumor formation than p53.
Suzuki et al. (2008) showed that Dlx5 (600028), Dlx6 (600030), p63, and Bmp7 (112267), a putative p63 target gene, were all expressed in developing mouse urethral plate. Targeted inactivation of p63, Bmp7, or both Dlx5 and Dlx6 resulted in abnormal urethra formation in mice.
The AER is a transitory multilayered ectoderm acting as a signaling center essential for distal limb development and digit patterning. Lo Iacono et al. (2008) stated that the normal stratified organization of the AER is compromised in p63 mutant limbs and in mouse Dlx5/Dlx6 double-knockout limbs. They found that p63 colocalized with Dlx5 and Dlx6 in the embryonic mouse AER and that p63 associated with the Dlx5 and Dlx6 promoters in vivo. Delta-N p63-alpha was the predominant p63 isoform expressed in developing limbs. Delta-N p63-alpha bound and activated transcription of Dlx5 and Dlx6 reporter constructs. Other delta-N isoforms were less active, and isoforms containing the N-terminal transactivation domain showed no activity with Dlx5 and Dlx6 reporters.
Su et al. (2010) generated mice lacking TAp63. In 2.5 years of study, both heterozygous and TAp63-null mice developed spontaneous carcinomas and sarcomas and had a significantly shorter life span than the wildtype cohort. Paradoxically, a larger proportion of TAp63-null mice (24%) were tumor-free compared with TAp63 heterozygous mice (15%). Su et al. (2010) concluded that their data suggested that TAp63 is a haploinsufficient tumor suppressor gene. Consistent with this finding, sarcomas and carcinomas from TAp63 heterozygous mice retained the wildtype allele of TAp63. TAp63 heterozygous and null mice developed highly metastatic tumors and 10% of these metastases were found in the brain, a rare finding in spontaneous mouse tumor models.
Huang et al. (2023) generated mice with a stop codon prior to the TID in exon 14 of the p63 gene, selectively altering the oocyte-specific p63-alpha isoform. Heterozygous mutant females were infertile, whereas mutant males were fertile. Ovary size in the mutant female mice was markedly reduced, and the number of follicles was substantially reduced at postnatal day 1 (P1), with follicles completely absent by P21. Oocyte numbers were reduced to approximately 40% of those of wildtype mice, and had completely disappeared by P10. The mutant females showed elevated FSH and decreased estradiol levels. The authors suggested that expression of mutant p63 lacking the TID resulted in rapid depletion of oocytes and loss of fertility, similar to the human POF phenotype. Immunofluorescence staining of P1 ovarian sections showed a significant increase in cleaved-PARP1 (173870)-positive oocytes in mutant ovaries compared to wildtype. Increased expression of Bax (600040), Puma (BBC3; 605854), and Noxa (PMAIP1; 604959) was observed, suggesting that deleting the TID of the p63 protein was sufficient to induce uncontrolled apoptosis of oocytes in primordial follicles without exogenous damage. In vitro analysis in SAOS-2 cells confirmed that activated p63 lacking the TID triggers downstream proapoptotic pathways, causing oocyte exhaustion and infertility.
In 3 unrelated patients with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous arg204-to-trp (R204W) mutation in the DNA binding domain of TP63. The mutation segregated with the disease in 2 families and was not found in normal controls. In the third family, the mutation occurred de novo.
Kosaki et al. (2008) reported a Japanese male infant with EEC3 who was found to be heterozygous for the R204W mutation. He had a classic phenotype with split hand-foot malformation and cleft lip and palate. His father, who was found to be somatic mosaic for the mutation, had split hand-foot malformation, no cleft lip or palate, and whorl-like streaky pigmentary patterns of the skin following Blaschko lines. He had gray hair on the right half of his scalp and brown thin hair on the left side. He also had enamel hypoplasia and partial anodontia. Extensive genetic analysis demonstrated that the father was mosaic for the mutation in peripheral blood and hair, although most of his sperm carried the mutation. Kosaki et al. (2008) concluded that the mutation was postzygotic in the father and resulted in gonosomal mosaicism.
In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous arg204-to-gln mutation in the core element II of the DNA binding domain of TP63. The mutation segregated with the disease and was not found in normal controls.
In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a heterozygous cys306-to-arg mutation in the core element IV of the DNA binding domain of TP63. The mutation was de novo and was not found in normal controls. Transactivation assays using cell lysates containing the cys306-to-arg mutation showed a total lack of transactivation activity.
In a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Celli et al. (1999) identified a 1-bp insertion (A) at nucleotide 1572 in exon 13 of the TP63 gene, resulting in a frameshift at codon 525 (tyr) and a premature stop codon in the same exon. The mutation was de novo.
In a family with split-hand/foot malformation (SHFM4; 605289) from South Africa, previously reported by Spranger and Schapera (1988), Ianakiev et al. (2000) identified a 724A-G transition in exon 5 of the p63 gene, predicted to cause a lys194-to-glu (K194E) amino acid substitution. This family, designated R, was of mixed ancestry from Cape Province. The spectrum of clinical manifestations was broad, ranging from the presence of a split hand in 1 individual to bilateral monodactyly and unilateral aplasia of the right lower extremity with a split left foot in another individual. No family members had any significant abnormalities other than those of the extremities.
In a family of mixed ancestry from Cape Province, South Africa, with split-hand/foot malformation (SHFM4; 605289), Ianakiev et al. (2000) identified a 982T-C transition in exon 7 of the TP63 gene, predicted to cause an arg280-to-cys (R280C) amino acid substitution. The phenotype in this family, designated A, ranged from severe 'lobster claw' malformations of the feet in 1 individual, to minor 3/4 syndactyly of the left foot appearing as the only manifestation in another individual. The daughter of the latter individual had distal duplications of her thumbs bilaterally with absence of the second and third phalanges of the right hand and an absent second phalanx with 3/4 syndactyly of the left hand. No members of the family had significant abnormality of the face, palate, skin, teeth, hair, or nails. No abnormalities of the mammary glands or nipples were noted.
Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome
In a study of 4 European families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Ianakiev et al. (2000) identified heterozygosity for 2 missense mutations in the TP63 gene: a G-to-A transition at nucleotide 980 in exon 7 that predicts an arg279-to-his (R279H) substitution, and a G-to-A transition at nucleotide 1065 in exon 8 that predicts an arg304-to-gln (R304Q) substitution (603273.0008).
Rapp-Hodgkin Syndrome
In a 25-year-old female with features consistent with Rapp-Hodgkin syndrome (RHS; 129400), Bougeard et al. (2003) identified heterozygosity for the R279H substitution. This residue corresponds to the R248 hotspot mutation in TP53 (see 191170), and occurs within the DNA-binding domain present within all of the TP63 isoforms. In vitro functional analysis showed that this mutation did not decrease the transcriptional activity of the TAp63-gamma isoform on a TP53 reporter system, but disrupted the dominant-negative activity of the delta-N-p63-alpha and -gamma isoforms on the transcriptional activity of TP53.
In a study of 4 European families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Ianakiev et al. (2000) identified heterozygosity for 2 missense mutations in the TP63 gene: a G-to-A transition at nucleotide 1065 in exon 8 that predicts an arg304-to-gln (R304Q) substitution, and a G-to-A transition at nucleotide 980 in exon 7 that predicts an arg279-to-his (R279H; 603273.0007) substitution.
In a 6-year-old patient with Hay-Wells syndrome (AEC; 106260) who lacked any limb defects, McGrath et al. (2001) identified an A-to-T transversion at nucleotide 1542 of the TP63 gene, resulting in a leu518-to-phe substitution in the sterile alpha motif (SAM) domain. Molecular modeling suggested that the substitution would alter protein-protein interactions. According the sequence reported by Yang et al. (1998), this mutation is designated leu514 to phe.
In a transactivation assay, Beaudry et al. (2009) demonstrated that TA-TP63-alpha-L514F was completely defective in activating the PERP (609301) luciferase reporter compared to wildtype. The authors hypothesized that specific protein-protein interactions needed for full PERP transactivation by TP63 are abolished when the structure of the sterile alpha motif (SAM) domain is compromised, as is the case with the L514F mutation.
In a 10-month-old infant with typical features of Hay-Wells syndrome (AEC; 106260), McGrath et al. (2001) identified a T-to-G transversion at nucleotide 1564 of the TP63 gene, resulting in a cys526-to-gly substitution in the sterile alpha motif (SAM) domain. Molecular modeling suggested that the substitution would alter protein-protein interactions. According the sequence reported by Yang et al. (1998), this mutation is designated cys522 to gly.
In a 10.5-year-old patient with features of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (103285), Amiel et al. (2001) described a heterozygous A-to-C transversion at position 16 in exon 3-prime of the TP63 gene, resulting in an asn6-to-his (N6H) substitution between the transactivation and DNA binding domains. The mutation affected exon 3-prime present only in the isotypes lacking the transactivation domain of the protein. The mutation was inherited from the healthy father, in whom freckling of the back and shoulders was the only feature of ADULT syndrome, and was absent from a panel of 250 control chromosomes. Amiel et al. (2001) considered incomplete penetrance as the most likely explanation.
In a patient (BX) with limb-mammary syndrome (LMS; 603543), who had bilateral split hand/foot malformation, isolated cleft palate, and normal hair, skin, and teeth, but absent nipples, van Bokhoven et al. (2001) identified heterozygosity for a de novo 2-bp deletion (1576_1577delTT) in exon 13 of the TP63 gene, resulting in a frameshift predicted to cause premature termination of the p63-alpha protein within the SAM domain. The numbering of the mutation is according to the sequence reported by Yang et al. (1998). The mutation was not found in the proband's unaffected parents. Guazzarotti et al. (2008) evaluated this patient at age 14 years for primary amenorrhea and found that, although she had normal development of external genitalia and pubic hair and normal morphology of the lower vaginal tract, she had absent uterus and ovaries; hormonal evaluation revealed hypergonadotropic hypogonadism with a very low plasma estrogen level.
In a patient (DW) with limb-mammary syndrome (LMS; 603543), who had bilateral split hand/foot malformation, absent lacrimal punctae, submucous cleft palate, bilateral ear pits, somewhat dry skin on the trunk, absent nipples, and anteriorly placed anus, van Bokhoven et al. (2001) identified heterozygosity for a de novo 2-bp deletion (1743delAA) in exon 14 of the TP63 gene, resulting in a frameshift predicted to cause premature termination of the p63-alpha protein. The numbering of the mutation is according to the sequence reported by Yang et al. (1998).
Duijf et al. (2002) reported a 2-generation family with acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome (103285) whose affected individuals were heterozygous for an arg298-to-gln (R298Q) mutation. The mutation is located in the DNA binding domain of p63; however, unlike mutations in EEC syndrome, the R298Q mutation does not impair DNA binding. Rather, the mutation confers novel transcription activation capacity on the delta-N-p63-gamma isoform, which normally does not possess such activity. The authors concluded that p63 contains a second transactivation domain which is normally repressed and can become activated by mutations in the DNA binding domain of p63.
Rinne et al. (2006) reported 2 unrelated families with ADULT syndrome in which affected members carried the R298Q mutation. The authors identified another mutation in the same codon, R298G (603273.0022), in a third family with ADULT syndrome.
In a 17-year-old boy with ectodermal dysplasia and arrhythmogenic right ventricular cardiomyopathy, Valenzise et al. (2008) identified the R298Q mutation in the TP63 gene. The patient presented with asthenia and dyspnea and was found to have ectodermal signs including hypodontia, lacrimal duct aplasia, dystrophic nails, sparse, fragile, and wiry hair, decreased sweating, and absent right nipple. He had normal hands and feet with no radiographic anomalies. Cardiologic findings were consistent with the diagnosis of arrhythmogenic right ventricular cardiomyopathy by morphologic, functional, electrocardiographic, and histologic features. A cardioverter defibrillator was implanted 1 year after diagnosis. His mother, who had absent nipples and hypodontia but no cardiac defects or arrhythmia, also carried the R298Q mutation.
In a Japanese girl with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292) who developed diffuse large B-cell type non-Hodgkin lymphoma, Akahoshi et al. (2003) identified heterozygosity for a 1079A-G transition in exon 8 of the TP63 gene, resulting in a germline asp312-to-gly (D312G) mutation. They speculated that p63 may exert a biologic function as a tumor suppressor and suggested that malignant lymphoma should be considered an important complication of EEC3, inasmuch as 2 previous reports had also documented an association of EEC syndrome with malignant lymphoma (Gershoni-Baruch et al., 1997; Ogutcen-Toller et al., 2000).
In a 32-year-old male with features consistent with Rapp-Hodgkin syndrome (RHS; 129400), Bougeard et al. (2003) identified heterozygosity for a 1-bp deletion (1709delA) in exon 14 of the TP63 gene, resulting in a stop codon 22 amino acids downstream of the normal stop codon. This mutation is located in the post-SAM region and is predicted to affect only the TP63-alpha isoforms.
In 2 sibs and their mother who had been diagnosed with Rapp-Hodgkin syndrome (RHS; 129400), Dianzani et al. (2003) identified a 1-bp deletion (1859delA) in exon 14 of the TP63 gene, causing a frameshift at codon 620 affecting the alpha tail. The mutation was not found in an unaffected sib. The mother's clinical history revealed that she had a slight ankyloblepharon on the right eye at birth which was surgically treated; Dianzani et al. (2003) suggested that ankyloblepharon-ectodermal defects-clefting syndrome (AEC; 106260) and RHS are the same clinical entity.
In a patient with ankyloblepharon-ectodermal defects-clefting syndrome (AEC; 106260) previously described by Bertola et al. (2000) and in a patient with Rapp-Hodgkin syndrome (RHS; 129400), Bertola et al. (2004) identified a 1529C-to-T transition in exon 12 of the TP63 gene, predicting an ile510-to-thr (I510T) substitution. Both cases were sporadic. Bertola et al. (2004) concluded that AEC and RHS represent variable expression of a single genetic disorder.
In a 14-year-old Thai boy with Rapp-Hodgkin syndrome (RHS; 129400), Kantaputra et al. (2003) identified heterozygosity for a 1633T-C transition in exon 13 of the TP63 gene, resulting in a ser545-to-pro (S545P) substitution in the fourth helix of the sterile alpha motif (SAM) domain.
In a patient with ADULT syndrome (103285), Slavotinek et al. (2005) identified a heterozygous 518G-A transition in exon 4 of the TP63 gene, resulting in a val114-to-met (V114M) substitution. The patient had fifth finger brachydactyly and camptodactyly, ulnar ray hypoplasia, and imperforate anus, suggesting phenotypic overlap with ulnar-mammary syndrome (181450).
In a 4-year-old Thai girl with orofacial cleft (OFC8; 618149), Leoyklang et al. (2006) found a heterozygous 937A-G transition in exon 8 of the TP63 gene, resulting in an arg313-to-gly (R313G) substitution at a highly conserved residue in the DNA binding domain. The patient had a surgically repaired bilateral complete cleft lip. The mutation was not found in her unaffected parents or in 1,000 control chromosomes.
In affected members of a Finnish family with ADULT syndrome (103285), Rinne et al. (2006) identified a heterozygous 892C-G transversion in the TP63 gene, resulting in an arg298-to-gly (R298G) substitution. This substitution occurs in the same codon as another variant reported in ADULT syndrome (R298Q; 603273.0014). In vitro functional expression studies showed that the R298G mutation resulted in increased transcription activation, similar to the R298Q mutation.
In a Mexican child with isolated unilateral split-hand malformation (SHFM4; 605289), Zenteno et al. (2005) identified a heterozygous 289C-T transition in exon 3 of the TP63 gene, resulting in an arg97-to-cys (R97C) substitution in the transactivation domain. The child also had a small scalp lesion, or aplasia cutis, which may or may not have been related to the TP63 mutation.
In affected individuals from 3 unrelated families with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), 2 of which were previously reported by O'Quinn et al. (1998), van Bokhoven et al. (2001) identified heterozygosity for a 797G-A transition in the TP63 gene, resulting in an arg227-to-gln (R227Q) substitution.
Sripathomsawat et al. (2011) provided follow-up of a remotely consanguineous Dutch family with EEC3, previously reported by Maas et al. (1996) and O'Quinn et al. (1998), in which affected members were heterozygous for the R227Q mutation. Twelve newly affected individuals were identified, with marked phenotypic variability. Limb defects were present in 12 of 26 affected members, including 6 with split hand/foot and 1 with mesoaxial polydactyly. Two had cleft lip/palate, and 3 had mild manifestations of this features, such as indentation of the upper vermilion border. One individual had features of the AEC syndrome (106260). Features of ectodermal dysplasia were also variable. Most had blonde, sparse hair with slow growth, thin nails, periorbital hyperpigmentation, and dental caries. Four had hypodontia, and 8 were edentulous on examination. Most notable, 12 of those affected had micturition difficulties, which tended to improve with age, and 1 had defecation difficulties. Sripathomsawat et al. (2011) emphasized that patients with EEC3 should have systematic dental examinations.
In a mother and daughter with ADULT syndrome (103285), Reisler et al. (2006) identified the R227Q mutation in exon 6 of the TP63 gene and suggested that there may be considerable overlap between the EEC and ADULT syndromes.
In affected members of 2 unrelated families with EEC syndrome, features of limb-mammary syndrome (LMS; 603543), and severe micturition difficulties, Maclean et al. (2007) identified the R227Q mutation in the TP63 gene. Noting that 4 of the 6 cases/families reported with this mutation had manifested similar urinary symptoms (see van Bokhoven et al., 2001), the authors suggested that this represents a genotype/phenotype correlation.
In a mother and daughter with Rapp-Hodgkin syndrome (RHS; 129400) associated with corneal dystrophy and premature menopause, Holder-Espinasse et al. (2007) identified heterozygosity for a 1-bp deletion (1783delC) in the TP63 gene, resulting in a frameshift and a protein that is 22 amino acids longer than wildtype. The authors stated that this was the first report of these associated age-related features in RHS.
In a Dutch mother and daughter with minimal manifestations of ADULT syndrome (103285), van Zelst-Stams and van Steensel (2009) identified heterozygosity for a 380C-T transition in the TP63 gene, resulting in a pro127-to-leu (P127L) substitution at a highly conserved residue in the C-terminal end of the proline-rich domain. The mutation was not found in 100 unrelated Dutch controls.
In an 11-year-old boy who displayed an overlapping phenotype with features of both ankyloblepharon-ectodermal defects-clefting syndrome (AEC; 106260) and Rapp-Hodgkin syndrome (RHS; 129400), Prontera et al. (2008) identified heterozygosity for an 11-bp duplication (1716dupCTCCCCTTCTC) in exon 14 of the TP63 gene, predicted to result in a protein that is 26 amino acids longer than wildtype. The mutation is located in the transcriptional inhibitory domain (TID) and is predicted to affect only the TP63-alpha isoforms. The patient was born with bilateral ankyloblepharon filiforme adnatum and submucous cleft palate and was diagnosed with AEC syndrome; however, he had only slight erythema of the scalp without infection or erosion or areas of eczematous skin. Upon reevaluation at age 11 years, he showed facial dysmorphism including high frontal hairline, hypoplastic alae nasi, pinched and narrow nose, midface hypoplasia with relative prognathism, and had hypohidrosis and syndactyly, features more suggestive of a diagnosis of RHS.
In a Thai father and his daughter with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (EEC3; 604292), Sripathomsawat et al. (2011) identified a heterozygous 680G-C transversion in exon 6 of the TP63 gene, resulting in an arg227-to-pro (R227P) substitution in a highly conserved residue. The mutation was not found in 100 Thai control individuals. The 4-year-old daughter had dry and sparse dark hair, left cleft lip and palate, depressed nasal bridge, slightly dry skin, and thin nails. She had split hands and split right foot, as well as syndactyly of the right fourth and fifth toes. Her father had normal dark hair, dry skin, split right hand, bifid right thumb, and flexion contracture of the distal phalanx of the left index finger. His second toes were small and slender, and he had underdeveloped toenails. The father had significant dental involvement, with enamel hypoplasia, extensive dental caries, hypodontia of the mandibular canines, generalized microdontia, prominent marginal ridges of permanent maxillary incisors, round-shaped permanent molars, and barrel-shaped permanent maxillary central incisors. Although the mutation affected the same residue as a mutation found in a Dutch family with EEC3 and significant micturition difficulties (R227Q; 603273.0024), neither of the Thai patients had micturition problems. Sripathomsawat et al. (2011) emphasized that patients with EEC3 should have systematic dental examinations.
In a family (CLP-1055) in which the proband and his father had orofacial cleft (OFC8; 618149), Basha et al. (2018) identified heterozygosity for a 2-bp duplication (c.819-820dupCC, NM_003722.4) in exon 6 of the TP63 gene, resulting in a frameshift and a premature termination codon (Gln274fsTer4) in the evolutionarily conserved DNA binding domain. mRNA studies demonstrated nonsense-mediated mRNA decay of the mutant allele. The mutation, which was found by exome sequencing, segregated with the phenotype in the family and was not present in the gnomAD database. The son had a unilateral right-sided cleft lip and his father had a unilateral left-sided cleft lip. Neither patient had any symptoms of other TP63 disorders.
In a 16-year-old girl (patient 8) with primary amenorrhea (POF21; 620311), Tucker et al. (2019) identified heterozygosity for a de novo c.1780C-T transition (c.1780C-T, NM_003722.4) in exon 14 of the TP63 gene, resulting in an arg594-to-ter (R594X) substitution within the sterile alpha motif, truncating TP63 before the transactivation inhibitory domain. The mutation was not found in her unaffected parents or in public variant databases.
In a 27-year-old Chinese woman (patient 5) with primary amenorrhea and nonvisualization of the ovaries on ultrasound, Huang et al. (2023) identified heterozygosity for the R594X mutation in the TP63 gene. The authors noted that the R594X variant was present at low minor allele frequency in the gnomAD and ExAC databases (MAFs, 0.00003290 and 0.00007419, respectively). Western blot analysis of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but barely detectable expression of the R594X mutant. BN-PAGE analysis suggested that the R594X mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R594X mutant.
In a woman (FRA125) with primary amenorrhea (POF21; 620311), Tucker et al. (2019) identified heterozygosity for a c.1794G-A transition (c.1794G-A, NM_003722.4) in exon 14 of the TP63 gene, resulting in a trp598-to-ter (W598X) substitution. Parental DNA status was not reported, but the mutation was not found in public variant databases.
In a 24-year-old woman and her paternal aunt with secondary amenorrhea and atrophic ovaries (POF21; 620311), Tucker et al. (2022) identified heterozygosity for a c.290G-C transversion (c.290G-C, NM_003722.5) in exon 3 of the TP63 gene, resulting in an arg97-to-pro (R97P) substitution at a highly conserved residue within the N-terminal TAD of the TAp63-alpha isoform. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R97P substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63.
In a 27-year-old woman with secondary amenorrhea and atrophic ovaries devoid of follicles (POF21; 620311), Tucker et al. (2022) identified heterozygosity for a paternally inherited c.1939C-T transition (c.1939C-T, NM_003722.5) in exon 14 of the TP63 gene, resulting in an arg647-to-cys (R647C) substitution at a highly conserved residue within the C-terminal TID. The mutation was not found in the gnomAD database. Analysis of the TP63 complex conformation using BN-PAGE showed that the R647C substitution disrupts TP63 dimerization, causing an open active tetramer conformation. Luciferase reporter assays revealed a significant increase in transcriptional activity with the R97P mutant compared to wildtype TP63.
In 3 unrelated Chinese women (patients 8, 9, and 10) with secondary amenorrhea and nonvisualization of the ovaries on ultrasound, Huang et al. (2023) identified heterozygosity for the R647C mutation in the TP63 gene. The R647C variant was not found in the ExAC database, but was present at low minor allele frequency in gnomAD (MAF, 0.00001316). Western blot of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but significantly reduced expression of the R647C mutant. BN-PAGE analysis suggested that the R647C mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the R647C mutant. Mice heterozygous for the R647C mutation showed accelerated oocyte loss, reduced fertility, and impaired oocyte quality, but the phenotypes were less severe than mice carrying a mutation that truncated the TID. The authors noted that this was consistent with patients carrying the R647C mutation presenting with secondary amenorrhea.
In a 32-year-old Chinese woman (patient 4) with primary amenorrhea (POF21; 620311), Huang et al. (2023) identified heterozygosity for a 1-bp deletion (c.1703delA, NM_003722.5) in exon 13 of the TP63 gene, causing a frameshift predicted to result in a premature termination codon (Gln568fsTer3). The mutation was not found in the ExAC or gnomAD databases. Western blot analysis of human SAOS-2 cells in which wildtype and mutant TP63 had been overexpressed showed high expression of wildtype protein but barely detectable expression of the Gln568fsTer3 mutant. BN-PAGE analysis suggested that the Gln568fsTer3 mutant disrupts the inactive TP63 conformation, forming a constitutively active tetramer. Luciferase reporter assays confirmed significantly increased transcriptional activity with the mutant compared to wildtype TP63, and apoptosis assays showed a significant increase in TUNEL-positive SAOS-2 cells overexpressing the Gln568fsTer3 mutant.
In 6 affected individuals over 2 generations of a Danish family with an atypical form of limb-mammary syndrome (LMS; 603543), Mathorne et al. (2020) identified heterozygosity for a c.1927C-T transition (c.1927C-T, NM_003722.4) in exon 14 of the TP63 gene, resulting in an arg643-to-ter (R643X) substitution within the transactivation inhibitory domain (TID). The mutation segregated with disease in the family and was not found in the gnomAD database.
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