Alternative titles; symbols
HGNC Approved Gene Symbol: PORCN
SNOMEDCT: 205573006;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:48,508,992-48,520,814 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Focal dermal hypoplasia | 305600 | X-linked dominant | 3 |
The Drosophila porcupine (Porc) gene encodes an endoplasmic reticulum transmembrane protein involved in processing of wingless proteins (see WNT1; 164820). By searching for homologs of Drosophila and mouse Porc, followed by PCR of adult hippocampus and a neuroblastoma cell line, Caricasole et al. (2002) cloned human PORC. Alternative splicing of exons 7 and 8 results in 4 PORC transcripts, PORCA through PORCD. Northern blot analysis detected a 1.8-kb transcript in human cell lines. RT-PCR detected variable expression of 4 PORC transcripts in most human tissues examined.
Wang et al. (2007) stated that PORCN has 5 transcript variants that encode 5 protein isoforms with tissue-specific variability and expression (PORCA-PROCE). To investigate how developmental expression of PORCN contributes to the specific defects in focal dermal hypoplasia (FDH; 300651), Wang et al. (2007) performed RNA in situ hybridization on embryonic day 12.5 and embryonic day 14.5 mouse embryos using a probe that detects all known mouse Porcn transcript variants. They detected Porcn and the distinctive peripheral pattern in cartilage primordia of long bones and digits, calvarian, facial skeleton, molar tooth bud, and the petrous part of the temporal bone. They also observed it in developing skin of the anterior body wall and limbs and at lower levels in developing cerebral cortex and retina.
Caricasole et al. (2002) found that overexpression of human PORCD in rat PC12 cells enhanced activity of a WNT7A (601570) expression construct.
Caricasole et al. (2002) determined that the PORCN gene contains 15 exons and spans about 12 kb. The first exon is noncoding, and the putative promoter region contains a TATA box and several SP1 (189906)-binding elements.
By genomic sequence analysis, Caricasole et al. (2002) mapped the PORCN gene to chromosome Xp11.23.
Focal dermal hypoplasia (FDH; 305600) is an X-linked dominant disorder characterized by patchy hypoplastic skin and digital, ocular, and dental malformations. In 2 unrelated females with focal dermal hypoplasia, Wang et al. (2007) used array comparative hybridization to identify a 219-kb deletion in Xp11.23 that encompassed 5 genes, including PORCN. FISH confirmed the deletion. There was 100% skewing of X chromosome inactivation (XCI) in peripheral blood lymphoblasts (PBL) DNA in both. The finding of 2 such nearly identical heterozygous genomic deletions may indicate that this is a common mutational mechanism for FDH, possibly mediated by low-copy repeat sequences. The authors raised the question of whether complex phenotypes caused by haploinsufficiency of other disease-associated genes in this region, such as EBP (300205), could result from this deletion. Wang et al. (2007) identified mutations in 10 of 15 females with FDH; see, e.g., 300651.0001-300651.0002. They also identified de novo mosaic mutations with overlapping wildtype and mutant sequencing profiles in all 3 male index FDH cases studied but not in their parents.
In 2 females with FDH, Grzeschik et al. (2007) identified deletions in Xp11.23 that overlapped by approximately 80 kb and included 4 genes, including PORCN. Grzeschik et al. (2007) concluded that FDH can be a component of a contiguous gene syndrome. They also noted markedly skewed X-chromosome inactivation. In 8 individuals with FDH, Grzeschik et al. (2007) identified several heterozygous nonsense mutations and 1 splice site mutation (e.g., 300651.0003-300651.0004).
Leoyklang et al. (2008) reported 3 unrelated Thai girls with sporadic FDH in whom they identified mutations in the PORCN gene (see, e.g., 300651.0005), confirming that PORCN is the gene responsible for FDH across different populations.
Bornholdt et al. (2009) performed molecular characterization of 24 unrelated FDH patients from different ethnic backgrounds and identified 23 different PORCN mutations: 3 were microdeletions encompassing PORCN as well as neighboring genes, and 12 (50%) of the 24 patients carried nonsense mutations resulting in loss of function. In 1 patient, a canonic splice acceptor site was mutated, and in 9 patients, 8 different missense mutations involving highly conserved amino acids (see, e.g., 300651.0005) were identified.
Froyen et al. (2009) analyzed the PORCN gene in 6 Finnish and 2 Belgian patients with FDH and identified a 150-kb deletion, encompassing PORCN and at least 5 other genes in a 13-year-old Finnish girl. In addition, they identified 2 different missense mutations, 1 in a 6-year-old Belgian girl and the other in a 16-year-old Finnish girl. Froyen et al. (2009) noted that the latter mutation (R365Q; 300651.0005) had previously been found in a Thai girl with a severe form of FDH by Leoyklang et al. (2008) and in a girl with a mild FDH phenotype by Bornholdt et al. (2009), and that the same arginine was found to be mutated to a glycine (R365G) in a male patient with FDH by Wang et al. (2007). Review of the 63 reported PORCN mutations, revealed that although mutations were scattered throughout the entire protein, there appeared to be a hotspot region between amino acids 349 and 365, with 11 mutations reported to date in that 16-amino acid stretch. Froyen et al. (2009) stated that these were the first causal PORCN mutations identified in the Finnish and Belgian FDH populations.
In a female with focal dermal hypoplasia (FDH; 305600), Wang et al. (2007) identified a heterozygous 1059_1071dup13 (T358Pfs65X) mutation in exon 12 of the PORCN gene. Her father was found to have very low signals for the mutant sequence superimposed on the wildtype sequence, suggesting somatic mosaicism. The daughter was mildly affected, with dental pitting and notching, telangiectatic and atrophic skin, a Blaschko-linear pattern, and ectrodactyly.
In 2 females with focal dermal hypoplasia (FDH; 305600), Wang et al. (2007) identified heterozygosity for a 178G-A transition in exon 3 of the PORCN gene, resulting in a gly60-to-arg (G60R) substitution.
In 2 unrelated females with focal dermal hypoplasia (FDH; 305600), Grzeschik et al. (2007) identified heterozygosity for a 370C-T transition in the PORCN gene, resulting in an arg124-to-ter (R124X) substitution.
In a female with focal dermal hypoplasia (FDH; 305600), Grzeschik et al. (2007) identified a heterozygous 222G-A transition in the PORCN gene, resulting in a trp74-to-ter (W74X) substitution.
In a 3.75-year-old Thai girl with a severe form of focal dermal hypoplasia (FDH; 305600), Leoyklang et al. (2008) identified heterozygosity for a 1094G-A transition in exon 13 of the PORCN gene, predicted to result in an arg365-to-gln (R365Q) substitution at an evolutionarily conserved residue. Features in this patient included developmental delay, bilateral clinical anophthalmos, protruding ears, surgically repaired left complete cleft lip and palate, hypodontia, notched incisors, split sternum, ectrodactyly of the right hand, bilateral syndactyly of toes, mild scoliosis, and linear and patchy dermal hypoplasia on the chest, back, and extremities. The mutation was not found in 100 ethnically matched control X chromosomes.
In a 2-month-old female infant with a mild FDH phenotype, Bornholdt et al. (2009) identified heterozygosity for the R365Q mutation in the PORCN gene. The patient, who was a postzygotic mosaic for the mutation, displayed unilateral linear skin lesions, patchy hairlessness, and absence deformities of bones. The mutation was not found in 100 unrelated controls.
In a 16-year-old Finnish girl with FDH, Froyen et al. (2009) identified a de novo R365Q mutation in the PORCN gene. The mutation was not found in 300 X chromosomes derived from Finnish and Belgian controls. The patient had linear atrophic skin lesions on her extremities and buttocks, light erythematous streaks on the face, and an atrophic spot on the right side of the chest, as well as syndactyly of right-sided fingers and toes and pseudoarthrosis of the right bifid clavicle. She developed a cataract in her colobomatous right eye, which was without vision at 16 years of age.
Bornholdt, D., Oeffner, F., Konig, A., Happle, R., Alanay, Y., Ascherman, J., Benke, P. J., Boente, M. C., van der Burgt, I., Chassaing, N., Ellis, I., Francisco, C. R. I., and 22 others. PORCN mutations in focal dermal hypoplasia: coping with lethality. Hum. Mutat. 30: E618-E628, 2009. Note: Electronic Article. Erratum: Hum. Mutat. 30: 1472-1473, 2009. [PubMed: 19309688] [Full Text: https://doi.org/10.1002/humu.20992]
Caricasole, A., Ferraro, T., Rimland, J. M., Terstappen, G. C. Molecular cloning and initial characterization of the MG61/PORC gene, the human homologue of the Drosophila segment polarity gene Porcupine. Gene 288: 147-157, 2002. [PubMed: 12034504] [Full Text: https://doi.org/10.1016/s0378-1119(02)00467-5]
Froyen, G., Govaerts, K., Van Esch, H., Verbeeck, J., Tuomi, M.-L., Heikkila, H., Torniainen, S., Devriendt, K., Fryns, J.-P., Marynen, P., Jarvela, I., Ala-Mello, S. Novel PORCN mutations in focal dermal hypoplasia. Clin. Genet. 76: 535-543, 2009. [PubMed: 19863546] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01248.x]
Grzeschik, K.-H., Bornholdt, D., Oeffner, F., Konig, A., Boente, M. del C., Fritz, B., Hertl, M., Grasshoff, U., Hofling, K., Oji, V., Paradisi, M., Schuchardt, C., Szalai, Z., Tadini, G., Traupe, H., Happle, R. Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia. Nature Genet. 39: 833-835, 2007. [PubMed: 17546031] [Full Text: https://doi.org/10.1038/ng2052]
Leoyklang, P., Suphapeetiporn, K., Wananukul, S., Shotelersuk, V. Three novel mutations in the PORCN gene underlying focal dermal hypoplasia. Clin. Genet. 73: 373-379, 2008. [PubMed: 18325042] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.00975.x]
Wang, X., Reid Sutton, V., Peraza-Llanes, J. O., Yu, Z., Rosetta, R., Kou, Y.-C., Eble, T. N., Patel, A., Thaller, C., Fang, P., Van den Veyver, I. B. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nature Genet. 39: 836-838, 2007. [PubMed: 17546030] [Full Text: https://doi.org/10.1038/ng2057]