Alternative titles; symbols
HGNC Approved Gene Symbol: PCNT
SNOMEDCT: 1208348002;
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38) : 21:46,324,156-46,445,769 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 21q22.3 | Microcephalic osteodysplastic primordial dwarfism, type II | 210720 | Autosomal recessive | 3 |
Eukaryotic chromosome segregation depends on mitotic spindle apparatus, a bipolar array of microtubules nucleated from centrosomes. Centrosomal microtubule nucleation requires attachment of gamma-tubulin (TUBG1; 191135) ring complexes to a salt-insoluble centrosomal core. In budding yeast, this attachment is provided by the coiled-coil protein Spc110p, which links the yeast gamma-tubulin complex to the core of the yeast centrosome.
Flory et al. (2000) showed that kendrin is a human homolog of yeast Spc110p. They identified kendrin by homology of its C-terminal calmodulin-binding site with that of Spc110p. The N-terminal regions of kendrin share significant sequence homology with pericentrin, a centrosome component known to interact with gamma-tubulin. (It was later determined that kendrin and pericentrin are identical.) Kendrin localizes specifically to centrosomes throughout the cell cycle. In mitotic human breast cancer cells containing abundant centrosome-like structures, Flory et al. (2000) found kendrin only at centrosomes associated with spindle microtubules.
By screening a human fetal liver cDNA expression library with anti-centrosome serum, followed by 5-prime RACE and rescreening a cDNA library with the RACE product, Li et al. (2001) isolated a cDNA encoding kendrin, which they called pericentrin-B because of its high sequence identity with pericentrin, then thought to be a separate protein. Immunofluorescence microscopy demonstrated that kendrin is expressed in centrosomes and is an essential component of the pericentriolar material (PCM). Immunoblot analysis showed that kendrin is expressed as a greater than 350-kD protein. Sequence analysis predicted that the 3,321-amino acid protein contains a large N-terminal coiled-coil domain of approximately 1,500 residues and a smaller C-terminal coiled-coil domain of approximately 500 amino acids. Both coiled-coil domains are flanked by non-coiled ends. Immunoprecipitation and immunoblot analysis indicated that kendrin complexes with PCM1 (600299) but not with gamma-tubulin. Functional analysis suggested that kendrin and PCM1 activities are not essential for the microtubule nucleation process.
Kantaputra et al. (2011) performed in situ hybridization analysis of lower molar tooth expression in wildtype mice, and observed that the first Pcnt signals were derived from tooth-presumptive epithelium at embryonic day 9.5. Pcnt was expressed in the thickened tooth epithelium and mesenchyme at E12.5, in the bud epithelium at embryonic day 13.5, and in the cap epithelium and dental papillae at embryonic day 14.5, with weak expression in both ameloblasts and odontoblasts at embryonic day 18.5.
By PCR amplification, Southern blot analysis, and fluorescence in situ hybridization, Chen et al. (1996) mapped the kendrin (PCNT) gene to 21q between PFKL (171860) at 21q22.3 and 21qter.
Rauch et al. (2008) demonstrated that absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes.
Using small interfering RNA (siRNA), Graser et al. (2007) found that depletion of pericentrin, CEP290 (610142), or CEP164 (614848) in human retinal pigment epithelial cells prevented serum starvation-induced formation of a primary cilium.
Using an siRNA screen, Graser et al. (2007) found that depletion of CNAP1 (CEP2; 609689), rootletin (CROCC; 615776), pericentrin, CEP68 (616889), or CEP215 (CDK5RAP2; 608201) reduced centrosome cohesion and caused centrosome splitting in U2OS, A549, and RPE1 cells. Depletion of CNAP1 and rootletin produced the most severe phenotype. Depletion of pericentrin caused loss of CEP215 from centrioles, but depletion of CEP215 had no effect on pericentrin. Graser et al. (2007) concluded that CEP215 and pericentrin functionally interact and influence centrosome cohesion through an indirect mechanism independent of CNAP1, rootletin, and CEP68.
Individuals with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720) have an average birth weight of less that 1500 g at term, an average adult height of 100 cm, a brain size comparable to that of a 3-month old but usually with near-normal intelligence, and a variety of associated bone abnormalities. Rauch et al. (2008) identified 29 different homozygous or compound heterozygous mutations in the PCNT gene in 25 patients with MOPD2. There were 12 stop mutations and 17 frameshift mutations (4 splice site mutations, 2 small insertions, 2 small deletions, and 1 exon deletion). Two mutations occurred twice in unrelated patients, namely, R1923X (605925.0004) and 841insG (605925.0005). In contrast, they identified no PCNT mutations in 27 patients with a clinical diagnosis of MOPD1 (210710), MOPD3 (see 210710), Seckel syndrome (see 210600), or unclassified growth retardation syndromes. Absence of the PCNT protein was confirmed by Western blot analysis of lymphoblastoid cell lines from 2 patients, and both investigated heterozygous parents of 1 of these patients showed reduced protein levels in lymphoblasts. Rauch et al. (2008) suggested that this may explain their finding of significant reduction of the mean height of heterozygous MOPD II parents.
Griffith et al. (2008) performed a SNP-microarray genomewide homozygosity scan on 2 consanguineous families from the Middle East that included individuals clinically diagnosed with Seckel syndrome and showing cellular evidence of defective ATR signaling (601215). They mapped the disorder in these families to chromosome 21q22.3 in the region of the PCNT gene. By sequencing the 47 coding exons of the PCNT gene in affected individuals from the 2 Middle Eastern families, they identified homozygous truncating mutations in both: E220X (605925.0001) in one and S629fs (605925.0002) in the other. From screening of additional cases, they identified another truncating mutation in the PCNT gene (605925.0003) in a consanguineous Moroccan family.
Willems et al. (2008) noted that mutations in the PCNT gene had been identified in 28 patients, including the 25 with MOPD II reported by Rauch et al. (2008) and the 3 diagnosed with Seckel syndrome reported by Griffith et al. (2008). They performed direct sequencing of PCNT in 21 patients and identified 9 distinct mutations in 4 of the 16 patients diagnosed with Seckel syndrome and in all 5 patients diagnosed with MOPD II. Clinical analysis of the 4 Seckel syndrome patients with PCNT mutations showed that all presented minor skeletal changes and a severe growth retardation more suggestive of MOPD II. Willems et al. (2008) concluded that, despite variable clinical severity, MOPD II is a genetically homogeneous condition due to loss of function of pericentrin. Thus, the patients reported by Griffith et al. (2008) with mutations in the PCNT gene can be considered to have MOPD II. In their full report, in which additional patients were studied, Willems et al. (2010) identified a total of 13 distinct mutations in the PCNT gene, including one in another patient diagnosed with Seckel syndrome (605925.0009); this patient also had minor skeletal changes and clinical features compatible with a diagnosis of MOPD II.
In a 3-year-old Italian boy who was diagnosed at birth with Seckel syndrome but in whom the diagnosis was later revised to MOPD II, Piane et al. (2009) identified homozygosity for a 1-bp insertion in the PCNT gene (605925.0012). Noting the phenotypic overlap between Seckel syndrome and MOPD II, the authors emphasized the need for reevaluation in patients since certain clinical features may not be evident at birth; they considered PCNT mutations to be the hallmark for a correct diagnosis of MOPD II.
In 4 patients from 2 unrelated Thai pedigrees with features of MOPD II as well as extreme microdontia and alveolar bone hypoplasia, Kantaputra et al. (2011) identified homozygosity or compound heterozygosity for mutations in the PCNT gene (605925.0004; 605925.0010-605925.0011).
In 2 unrelated patients with MOPD II from the Druze population in Israel, Weiss et al. (2020) identified homozygosity for a splice site mutation in the PCNT gene (605925.0013). The mutation was reported in heterozygous state in 4 individuals from South Asia in the gnomAD database (allele frequency of 0.0001) and was not present in the Greater Middle East Variome Project database. Screening of 150 DNA samples from different paternal households in the Druze population revealed 5 mutation carriers, resulting in a carrier rate of 1:30. The affected patients and carriers were from 7 different Druze villages, leading Weiss et al. (2020) to conclude that the mutation was a founder mutation and not a private mutation related to a certain village or family. Weiss et al. (2020) identified a haplotype shared by the 2 patients and an unrelated carrier which was localized to 450 kb in the subtelomeric region of chromosome 21q22.3.
In affected male and female members of a consanguineous Saudi Arabian family who had been diagnosed with Seckel syndrome (see 210600), Griffith et al. (2008) identified homozygosity for a glu220-to-ter (E220X) mutation in the PCNT gene. Both patients were born at 33 weeks' gestation and were small at birth. One of them had diabetes mellitus. The parents in each case were heterozygous for the mutation, which was not found in over 200 control alleles. Willems et al. (2008) later reported that patients with mutations in the PCNT gene have type II microcephalic osteodysplastic primordial dwarfism (MOPD2; 210720), a clinically variable but genetically homogeneous condition.
In a female diagnosed with Seckel syndrome (see 210600), born of first-cousin parents in Kuwait, Griffith et al. (2008) identified homozygosity for a single-basepair deletion in exon 12 of the PCNT gene that led to a frameshift which was predicted to result in premature protein termination after an additional 65 amino acids (S629fs). The parents were heterozygous for the mutation, which was not found in over 200 control alleles. Willems et al. (2008) later reported that patients with mutations in the PCNT gene have type II microcephalic osteodysplastic primordial dwarfism (MOPD2; 210720), a clinically variable but genetically homogeneous condition.
In a male diagnosed with Seckel syndrome (see 210600), born of first-cousin parents in Morocco, Griffith et al. (2008) identified homozygosity for a 1-bp insertion in exon 18 of the PCNT gene, resulting in a frameshift at codon 1190 (C1190fs). The parents were heterozygous for the mutation, which was not found in over 200 control alleles. Willems et al. (2008) later reported that patients with mutations in the PCNT gene have type II microcephalic osteodysplastic primordial dwarfism (MOPD2; 210720), a clinically variable but genetically homogeneous condition.
In 2 patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720) from consanguineous but unrelated families, one of Omani descent and the other of Pakistani descent, Rauch et al. (2008) identified homozygosity for a 5767C-T transition in the PCNT gene, resulting in an arg1923-to-ter (R1923X) substitution. The patients, aged 5.5 and 1.5 years, were born prematurely, one at 34 and the other at 32 weeks' gestation, with severe intrauterine growth retardation. Both had severe short stature, extreme microcephaly, and mild developmental delay.
In a Thai brother and sister with features of MOPD2 as well as extreme microdontia and alveolar bone hypoplasia, originally reported by Kantaputra (2002), Kantaputra et al. (2011) identified compound heterozygosity for the R1923X mutation in the PCNT gene and a 3-bp deletion (9460delAAG; 605925.0010) in exon 43, predicted to result in deletion of lys315.
In 2 presumably unrelated Turkish patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), one from a consanguineous and the other from an apparently nonconsanguineous union, Rauch et al. (2008) identified homozygosity for a 1-bp insertion, 841_842insG, resulting in a frameshift at arg281 and a termination codon at position 327 (Arg281fsTer327). The patient from the nonconsanguineous union was born at 35 weeks' gestation weighing 1300 g, and the other patient was born at 40 weeks' gestation weighing 1320 g. The patients, aged 12 and 5.5 years, had severe short stature and extreme microcephaly with mild developmental delay. Both also had multiple brain aneurysms and moyamoya disease (see 252350). Further analyses suggested that this mutation was transmitted through an unknown common ancestor because both patients were identical for all polymorphic sites identified within the PCNT region.
In a 12-year-old Turkish girl with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), whose parents were consanguineous, Rauch et al. (2008) identified homozygosity for a 3109G-T transversion in the PCNT gene, resulting in a glu1037-to-ter (E1037X) substitution. The child was born at 34 weeks' gestation weighing only 880 g. She had severe short stature, extreme microcephaly, multiple brain aneurysms, moyamoya disease, and mild developmental delay.
In a male patient from Turkey with the diagnosis of MOPD2, Willems et al. (2010) identified homozygosity for the E1037X mutation.
In a 12.5-year-old girl of consanguineous Kurdish descent with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), Rauch et al. (2008) identified homozygosity for a large deletion extending from IVS30 at nucleotide 84 to IVS34 at nucleotide 569, which resulted in a frameshift leading to a premature termination codon at amino acid 2317 (IVS30-84_IVS31-569del). The child was born at term weighing 1200 g. She was -9 SD in height and -8.7 SD for head circumference. She had moyamoya disease and no developmental delay.
In 2 children with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), aged 6.5 and 5 years, in a consanguineous Dutch family, Rauch et al. (2008) identified homozygosity for an 8752C-T transition in the PCNT gene, resulting in an arg2918-to-ter (R2918X) substitution. The children showed severe intrauterine growth retardation at birth with extreme short stature and microcephaly. Both had enlarged ventricles and both showed severe developmental delay.
In a patient with the diagnosis of Seckel syndrome (see 210600), Willems et al. (2010) identified homozygosity for a 3840G-C transversion affecting the last base of exon 19 of the PCNT gene, resulting in an apparent missense mutation, gln1280-to-his (Q2280H). The mutation was predicted to alter splicing. This was confirmed by sequence analysis of RT-PCR products which demonstrated exon 19 skipping, predictive of a premature termination of translation (Pro1204GlyfsTer11). The clinical analysis of this patient showed that she presented minor skeletal changes and clinical features compatible with the diagnosis of type II microcephalic osteodysplastic primordial dwarfism (MOPD2; 210720).
For discussion of the 3-bp deletion in the PCNT gene (9460delAAG) that was found in compound heterozygous state in a brother and sister with features of microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720) by Kantaputra et al. (2011), see 605925.0004.
In male and female third cousins with features of microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720) as well as extreme microdontia and alveolar bone hypoplasia, originally reported by Kantaputra et al. (2004), Kantaputra et al. (2011) identified homozygosity for a 3460G-T transversion in exon 17 of the PCNT gene, resulting in a glu1154-to-ter (E1154X) substitution predicted to cause premature termination of the protein. The unaffected parents were each heterozygous for the mutation.
In a 3-year-old Italian boy with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), Piane et al. (2009) identified homozygosity for a 1-bp insertion (1527_1528insA) in exon 10 of the PCNT gene, causing a frameshift predicted to result in a premature termination codon (Thr510fs). (The protein change was incorrectly published as Treo510fs.) His unaffected parents were heterozygous for the mutation.
In 2 unrelated patients from the Druze population in Israel with microcephalic osteodysplastic primordial dwarfism type II (MOPD2; 210720), Weiss et al. (2020) identified homozygosity for a G-A transition in the -1 position of intron 17 (c.3465-1G-A, NM_006031.5) of the PCNT gene. In patient 1 the mutation was identified by whole-exome sequencing, and in patient 2 it was identified by direct sequencing of the PCNT gene. The parents of patient 1 were mutation carriers. The c.3465-1G-A mutation was reported in heterozygous state in 4 individuals from South Asia in the gnomAD database (allele frequency of 0.0001) and was not present in the Greater Middle East Variome Project database. Sequencing of lymphoblastoid cell cDNA from patient 1 and his parents revealed a 2-bp deletion at the beginning of exon 18 due to the activation of a cryptic splice site, resulting in a frameshift and premature termination (Ala1157ProfsTer36). Weiss et al. (2020) concluded that this is a founder mutation.
Chen, H., Gos, A., Morris, M. A., Antonarakis, S. E. Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter. Genomics 35: 620-624, 1996. [PubMed: 8812505] [Full Text: https://doi.org/10.1006/geno.1996.0411]
Flory, M. R., Moser, M. J., Monnat, R. J., Jr., Davis, T. N. Identification of a human centrosomal calmodulin-binding protein that shares homology with pericentrin. Proc. Nat. Acad. Sci. 97: 5919-5923, 2000. [PubMed: 10823944] [Full Text: https://doi.org/10.1073/pnas.97.11.5919]
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Kantaputra, P. N. Apparently new osteodysplastic and primordial short stature with severe microdontia, opalescent teeth, and rootless molars in two siblings. Am. J. Med. Genet. 111: 420-428, 2002. [PubMed: 12210304] [Full Text: https://doi.org/10.1002/ajmg.10589]
Kantaputra, P., Tanpaiboon, P., Porntaveetus, T., Ohazama, A., Sharpe, P., Rauch, A., Hussadaloy, A., Thiel, C. T. The smallest teeth in the world are caused my mutations in the PCNT gene. Am. J. Med. Genet. 155A: 1398-1403, 2011. [PubMed: 21567919] [Full Text: https://doi.org/10.1002/ajmg.a.33984]
Li, Q., Hansen, D., Killilea, A., Joshi, H. C., Palazzo, R. E., Balczon, R. Kendrin/pericentrin-B, a centrosome protein with homology to pericentrin that complexes with PCM-1. J. Cell. Sci. 114: 797-809, 2001. [PubMed: 11171385] [Full Text: https://doi.org/10.1242/jcs.114.4.797]
Piane, M., Della Monica, M., Piatelli, G., Lulli, P., Lonardo, F., Chessa, L., Scarano, G. Majewski osteodysplastic primordial dwarfism type II (MOPD II) syndrome previously diagnosed as Seckel syndrome: report of a novel mutation of the PCNT gene. Am. J. Med. Genet. 149A: 2452-2456, 2009. [PubMed: 19839044] [Full Text: https://doi.org/10.1002/ajmg.a.33035]
Rauch, A., Thiel, C. T., Schindler, D., Wick, U., Crow, Y. J., Ekici, A. B., van Essen, A. J., Goecke, T. O., Al-Gazali, L., Chrzanowska, K. H., Zweier, C., Brunner, H. G., and 18 others. Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science 319: 816-819, 2008. [PubMed: 18174396] [Full Text: https://doi.org/10.1126/science.1151174]
Weiss, K., Ekhilevitch, N., Cohen, L., Bratman-Morag, S., Bello, R., Martinez, A. F., Hadid, Y., Shlush, L. I., Kurolap, A., Paperna, T., Mory, A., Baris, H. N., Muenke, M. Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population. Europ. J. Med. Genet. 63: 103643, 2020. Note: Electronic Article. [PubMed: 30922925] [Full Text: https://doi.org/10.1016/j.ejmg.2019.03.007]
Willems, M., Genevieve, D., Borck, G., Baujat, G., Gerard, M., Heron, D., Leheup, B., Le Merrer, M., Verloes, A., Colleaux, L., Munnich, A., Cormier-Daire, V. Pericentrin molecular analysis in 22 Seckel/MOPDII patients. (Abstract) 58th Annual Meeting, American Society of Human Genetics, Philadelphia 2008. P. 91.
Willems, M., Genevieve, D., Borck, G., Baumann, C., Baujat, G., Bieth, E., Edery, P., Farra, C., Gerard, M., Heron, D., Leheup, B., Le Merrer, M., Lyonnet, S., Martin-Coignard, D., Mathieu, M., Thauvin-Robinet, C., Verloes, A., Colleaux, L., Munnich, A., Cormier-Daire, V. Molecular analysis of pericentrin gene (PCNT) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families. J. Med. Genet. 47: 797-802, 2010. [PubMed: 19643772] [Full Text: https://doi.org/10.1136/jmg.2009.067298]