HGNC Approved Gene Symbol: PCDH15
Cytogenetic location: 10q21.1 Genomic coordinates (GRCh38): 10:53,802,771-55,627,942 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q21.1 | Deafness, autosomal recessive 23 | 609533 | Autosomal recessive | 3 |
| Usher syndrome, type 1D/F digenic | 601067 | Autosomal recessive; Digenic recessive | 3 | |
| Usher syndrome, type 1F | 602083 | Autosomal recessive | 3 |
Using a mouse Pcdh15 cDNA probe to screen a human genomic P1-derived artificial chromosome (PAC) library, Alagramam et al. (2001, 2001) identified the human PCDH15 gene. The CDH15 cDNA contains an open reading frame (ORF) that encodes 1,955 amino acids (Alagramam et al., 2001). The predicted protein has 11 cadherin repeats, 1 transmembrane domain and a cytoplasmic domain that contains 2 proline-rich regions. By Northern blot analysis, Alagramam et al. (2001) demonstrated PCDH15 expression in human adult brain, lung, and kidney. Expression in human fetal brain was assumed since the human PCDH15 cDNA was obtained by screening a fetal brain library. Additional experiments by RT-PCR and direct sequencing revealed expression in other human adult tissues and human fetal cochlea. Immunohistochemistry detected PCDH15 expression in the inner and outer synaptic layers and the nerve fiber layer in human adult and fetal retinas. Additional reactivity in the region of the outer limiting membrane/photoreceptor cell inner segments was observed in adult but not fetal retina. In human fetal cochlea, Alagramam et al. (2001) detected PCDH15 expression in the supporting cells and outer sulcus cells, as well as in the spiral ganglion.
Using RT-PCR, Alagramam et al. (2007) identified 2 minor splice variants of mouse Pcdh15, one that skipped exon 2 and another that skipped exons 2 and 4.
The PCSH15 gene encodes encodes a variety of isoforms with 3 to 11 ectodomains, a transmembrane domain, and a C-terminal cytoplasmic domain (CD). Ahmed et al. (2008) identified 4 additional exons in the PCDH15 gene, which encode 2 novel conserved cytoplasmic domains CD2 and CD3. The amino acid sequences of CD1, CD2, and CD3 are entirely different. PCDH15-CD1 showed a limited pattern of expression and was detected in human testis, retina, and cochlea. PCDH15-CD2 expression was present in the human heart, kidney, thymus, spleen, testis, retina and cochlea. PCDH15-CD3 was widely transcribed and detected in almost all of 18 tissues tested.
The human PCDH15 gene contains 33 exons and spans approximately 1.6 Mb of genomic DNA (Ahmed et al., 2001). Only the first 2 exons are situated in the Usher syndrome type IF (USH1F; 602083) critical region defined by one of the Pakistani families studied. The start codon is at 396 bp in exon 2 and the stop codon is at 6,263 bp in exon 33.
Ahmed et al. (2001) stated that 3 genes are nested in the introns of PCDH15: calcium/calmodulin-dependent protein kinase type II, presumably CAMKG (602123), known to map to 10q22; N-deacetylase/N-sulfotransferase 2 (NDST2; 603268), which maps to 10q22; and plasminogen-activator, urokinase (PLAU; 191840), previously thought to reside in 10q24.
Alagramam et al. (2007) determined that the promoter region of the PCDH15 gene contains a CpG island, but no TATAA or CAAT sequences. They identified suppressor and enhancer elements within the PCDH15 promoter.
Ahmed et al. (2008) identified 4 additional exons in the PCDH15 gene, for a total of 39 exons.
Alagramam et al. (2001) mapped the PCDH15 gene to chromosome 10q21-q22.
Alagramam et al. (2001) demonstrated PCDH15 expression in both retina and cochlea by RT-PCR and immunohistochemistry.
Ahmed et al. (2003) localized protocadherin-15 to inner ear hair cell stereocilia and to retinal photoreceptors by immunocytochemistry. The results further strengthened the importance of protocadherin-15 in the morphogenesis and cohesion of stereocilia bundles and retinal photoreceptor cell maintenance or function.
Kazmierczak et al. (2007) demonstrated that CDH23 (605516) and PCDH15, 2 cadherins linked to inherited forms of deafness in humans, interact to form tip links, extracellular filaments that connect the stereocilia and are thought to gate the mechanoelectrical transduction channel. Immunohistochemical studies using rodent hair cells showed that CDH23 and PCDH15 localized to the upper and lower part of tip links, respectively. The amino termini of the 2 cadherins colocalized on tip link filaments. Biochemical experiments showed that CDH23 homodimers interact in trans with PCDH15 homodimers to form a filament with structural similarity to tip links. Ions that affected tip link integrity and a mutation in PCDH15 that causes a recessive form of deafness (see DFNB23, 609533) disrupted interactions between CDH23 and PCDH15. Kazmierczak et al. (2007) concluded that their studies defined the molecular composition of tip links and provided a conceptual base for exploring the mechanisms of sensory impairment associated with mutations in CDH23 and PCDH15.
Crystal Structure
Sotomayor et al. (2012) combined crystallography, molecular dynamics simulations, and binding experiments to characterize the protocadherin-15-cadherin-23 (605516) bond. They found a unique cadherin interaction mechanism in which the 2 most N-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predicted that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex was shown to become unstable in response to calcium removal owing to increased flexure of calcium-free cadherin repeats. Finally, Sotomayor et al. (2012) used structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function.
Usher Syndrome Type IF
Ahmed et al. (2001) identified truncating mutations in the PCDH15 gene (605514.0001-605514.0002) in affected members of 2 families segregating Usher syndrome type IF (USH1F; 602083). Northern blot analysis showed expression in the retina, consistent with the pathogenetic role of the PCDH15 gene in retinitis pigmentosa associated with USH1F.
In cell culture studies, Rebibo-Sabbah et al. (2007) demonstrated that aminoglycosides suppressed translation of several PCDH15 nonsense mutations identified in patients with Usher syndrome type 1F. The aminoglycosides resulted in variable full-length protein levels resulting from partial read-through of the nonsense mutations. Rebibo-Sabbah et al. (2007) postulated that such treatment could potentially delay the progression of retinitis pigmentosa in patients with the disorder.
Ahmed et al. (2008) identified mutations in the PCDH15 gene in 7 of 12 consanguineous Pakistani families with USH1. Six mutations were novel (see, e.g., 605514.0009). The remaining 5 families showed linkage to chromosome 10q21, but no pathogenic mutations in the PCDH15 gene were identified.
Autosomal Recessive Deafness 23
Ahmed et al. (2003) demonstrated that nonsyndromic autosomal recessive deanfess-23 (DFNB23; 609533) is caused by biallelic mutation in the PCDH15 gene (see 605514.0006-605514.0007). They suggested a genotype-phenotype correlation in which hypomorphic alleles of the PCDH15 gene cause nonsyndromic hearing loss, whereas more severe mutations in this gene result in USH1F.
Usher Syndrome Type ID/F
Zheng et al. (2005) reported 3 families with Usher syndrome type I (see 601067) in which affected members carried mutations in both CDH23 (605516) and PCDH15, thus supporting a digenic model for some individuals with this phenotype. Based on an animal model, the authors concluded that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.
The neuroepithelia of the inner ear contain hair cells that function as mechanoreceptors to transduce sound and motion signals. Mutations affecting these neuroepithelia cause deafness and vestibular dysfunction in humans. Ames waltzer (av) is a recessive mutation in mice that causes deafness and a balance disorder associated with degeneration of inner ear neuroepithelia. Alagramam et al. (2001) identified Pcdh15 as the gene that harbors the av mutation in mice. Cochlear hair cells in the av mutants showed abnormal stereocilia by 10 days after birth.
Zheng et al. (2005) generated mice that were heterozygous for both Cdh23(v-2J) (605516) and Pcdh15(av-3J) mutations on a uniform C57BL/6J background. Significant levels of hearing loss were detected in these mice when compared to age-matched single heterozygous animals or normal controls, which supported a digenic model of hearing loss. Cytoarchitectural defects in the cochlea of digenic heterozygotes, including degeneration of the stereocilia and a base-apex loss of hair cells and spiral ganglion cells, were consistent with the observed age-related hearing loss of these mice beginning with the high frequencies. The authors noted that while hearing loss was progressive in these animals, humans with heterozygosity for both CDH23 and PCDH15 mutations are congenitally deaf. Zheng et al. (2005) concluded that CDH23 and PCDH15 play an essential long-term role in maintaining the normal organization of the stereocilia bundle.
In a consanguineous Pakistani family segregating Usher syndrome type IF (USH1F; 602083), Ahmed et al. (2001) found a homozygous IVS27-2A-G splice site mutation in the PCDH15 gene.
In a consanguineous Pakistani family, Ahmed et al. (2001) identified a homozygous arg3-to-ter (R3X) missense mutation in the PCDH15 gene as the cause of Usher syndrome type IF (USH1F; 602083).
In a Hutterite family from Alberta segregating Usher syndrome type IF (USH1F; 602083), Alagramam et al. (2001) identified a homozygous 1-bp deletion of T at nucleotide 1471 in exon 10 of the PCDH15 gene, creating a frameshift and premature stop codon after amino acid 419 in exon 11.
Among 1,524 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 38 heterozygotes and no homozygotes for the 1471delT mutation in the PCDH15 gene, for a frequency of 0.025, or 1 in 40. This is a private mutation in the Hutterite population.
Ben-Yosef et al. (2003) identified a homozygous arg245-to-ter (R245X) mutation in the PCDH15 gene in cases of Usher syndrome type I (USH1F; 602083) in Ashkenazi Jews. The R245X carrier frequencies (0.79 to 2.48%) were similar to the carrier frequencies of other genetic disorders for which routine screening is performed in this population, such as Tay-Sachs disease (3-4%), Gaucher disease (4-6%), and Canavan disease (1-2%). No R245X carriers were detected among other Jewish or non-Jewish population controls, indicating that this mutation may be unique to Ashkenazi Jews.
In a patient from the U.S. with Usher syndrome type IF (USH1F; 602083), Ouyang et al. (2005) identified heterozygosity for a 3-bp deletion (5601-5603delAAC) in exon 33 of the PCDH15 gene, resulting in deletion of threonine-1867. The 3-bp deletion was identified in compound heterozygosity with a PCDH15 missense mutation in another patient with USH1F. The mutation accounted for 2 (33%) of 6 mutant alleles identified by Ouyang et al. (2005) at the PCDH15 locus.
Zheng et al. (2005) identified 2 patients with a diagnosis of Usher syndrome type I (see 601067) who carried this deletion in heterozygosity, in combination with an additional mutation in the CDH23 gene: a single-basepair deletion (193delC; 605516.0011) and a missense mutation (T1209A; 605516.0013), respectively. The T1209A mutation in the CDH23 gene was later reclassified as a variant of unknown function.
In affected members of a family with severe to profound sensorineural hearing loss and no history of nyctalopia (DFNB23; 609533), Ahmed et al. (2003) identified a homozygous 785G-A transition in exon 8 of the PCDH15 gene, resulting in a gly262-to-asp (G262D) substitution.
In a family segregating profound autosomal recessive deafness (DFNB23; 609533), Ahmed et al. (2003) found that affected individuals were homozygous for a 400C-G transversion in exon 5 of the PCDH15 gene, resulting in an arg134-to-gly substitution.
In a proband with a diagnosis of Usher syndrome type I (see 601067), Zheng et al. (2005) detected a 1-bp deletion in exon 2 of the PCDH15 gene (16delT) in compound heterozygosity with a mutation in the CDH23 gene (R3189W; 605516.0012). The proband's brother, who had normal hearing, carried the 16delT mutation in heterozygosity. The PCDH15 16delT mutation causes a frameshift leading to an altered amino acid sequence from codon 6, followed by a premature termination at codon 11 in the predicted signal peptide of the protein.
In affected members of a consanguineous Pakistani family with Usher syndrome type IF (USH1F; 602083), Ahmed et al. (2008) identified a homozygous 1940C-G transversion in the PCDH15 gene, resulting in a ser647-to-ter (S647X) substitution predicted to truncate the protein in the EC6 domain.
In affected members of a consanguineous family from Newfoundland, Canada, with isolated deafness (DFNB23; 609533), Doucette et al. (2009) identified a homozygous 1583T-A transversion in the PCDH15 gene, resulting in a val528-to-asp (V528D) substitution in the highly conserved fifth ectodomain region. The hearing loss was neurosensory, prelingual, and severe to profound. Ancestors of the family had migrated from England in the early 1800s to settle a fishing 'outport' on Newfoundland's southern coast. Detailed examination of 2 homozygous carriers in middle age showed no evidence of Usher syndrome and no vestibular abnormalities.
Ahmed, Z. M., Riazuddin, S., Ahmad, J., Bernstein, S. L., Guo, Y., Sabar, M. F., Sieving, P., Riazuddin, S., Griffith, A. J., Friedman, T. B., Belyantseva, I. A., Wilcox, E. R. PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum. Molec. Genet. 12: 3215-3223, 2003. [PubMed: 14570705] [Full Text: https://doi.org/10.1093/hmg/ddg358]
Ahmed, Z. M., Riazuddin, S., Aye, S., Ali, R. A., Venselaar, H., Anwar, S., Belyantseva, P. P., Qasim, M., Riazuddin, S., Friedman, T. B. Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome. Hum. Genet. 124: 215-223, 2008. [PubMed: 18719945] [Full Text: https://doi.org/10.1007/s00439-008-0543-3]
Ahmed, Z. M., Riazuddin, S., Bernstein, S. L., Ahmed, Z., Khan, S., Griffith, A. J., Morell, R. J., Friedman, T. B., Riazuddin, S., Wilcox, E. R. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet. 69: 25-34, 2001. [PubMed: 11398101] [Full Text: https://doi.org/10.1086/321277]
Alagramam, K. N., Miller, N. D., Adappa, N. D., Pitts, D. R., Heaphy, J. C., Yuan, H., Smith, R. J. Promoter, alternative splice forms, and genomic structure of protocadherin 15. Genomics 90: 482-492, 2007. [PubMed: 17706913] [Full Text: https://doi.org/10.1016/j.ygeno.2007.06.007]
Alagramam, K. N., Murcia, C. L., Kwon, H. Y., Pawlowski, K. S., Wright, C. G., Woychik, R. P. The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nature Genet. 27: 99-102, 2001. [PubMed: 11138007] [Full Text: https://doi.org/10.1038/83837]
Alagramam, K. N., Yuan, H., Kuehn, M. H., Murcia, C. L., Wayne, S., Srisailpathy, C. R. S., Lowry, R. B., Knaus, R., Van Laer, L., Bernier, F. P., Schwartz, S., Lee, C., Morton, C. C., Mullins, R. F., Ramesh, A., Van Camp, G., Hageman, G. S., Woychik, R. P., Smith, R. J. H. Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum. Molec. Genet. 10: 1709-1718, 2001. Note: Erratum: Hum. Molec. Genet. 10: 2603 only, 2001. [PubMed: 11487575] [Full Text: https://doi.org/10.1093/hmg/10.16.1709]
Ben-Yosef, T., Ness, S. L., Madeo, A. C., Bar-Lev, A., Wolfman, J. H., Ahmed, Z. M., Desnick, R. J., Willner, J. P., Avraham, K. B., Ostrer, H., Oddoux, C., Griffith, A. J., Friedman, T. B. A mutation of PCDH15 among Ashkenazi Jews with the type 1 Usher syndrome. New Eng. J. Med. 348: 1664-1670, 2003. [PubMed: 12711741] [Full Text: https://doi.org/10.1056/NEJMoa021502]
Chong, J. X., Ouwenga, R., Anderson, R. L., Waggoner, D. J., Ober, C. A population-based study of autosomal-recessive disease-causing mutations in a founder population. Am. J. Hum. Genet. 91: 608-620, 2012. [PubMed: 22981120] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.007]
Doucette, L., Merner, N. D., Cooke, S., Ives, E., Galutira, D., Walsh, V., Walsh, T., MacLaren, L., Cater, T., Fernandez, B., Green, J. S., Wilcox, E. R., Shotland, L. I., Li, X. C., Lee, M., King, M.-C., Young, T.-L. Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15. Europ. J. Hum. Genet. 17: 554-564, 2009. Note: Erratum: Europ. J. Hum. Genet. 17: 1363 only, 2009. [PubMed: 19107147] [Full Text: https://doi.org/10.1038/ejhg.2008.231]
Kazmierczak, P., Sakaguchi, H., Tokita, J., Wilson-Kubalek, E. M., Milligan, R. A., Muller, U., Kachar, B. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449: 87-91, 2007. [PubMed: 17805295] [Full Text: https://doi.org/10.1038/nature06091]
Ouyang, X. M., Yan, D., Du, L. L., Hejtmancik, J. F., Jacobson, S. G., Nance, W. E., Li, A. R., Angeli, S., Kaiser, M., Newton, V., Brown, S. D. M., Balkany, T., Liu, X. Z. Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population. Hum. Genet. 116: 292-299, 2005. [PubMed: 15660226] [Full Text: https://doi.org/10.1007/s00439-004-1227-2]
Rebibo-Sabbah, A., Nudelman, I., Ahmed, Z. M., Baasov, T., Ben-Yosef, T. In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome. Hum. Genet. 122: 373-381, 2007. [PubMed: 17653769] [Full Text: https://doi.org/10.1007/s00439-007-0410-7]
Sotomayor, M., Weihofen, W. A., Gaudet, R., Corey, D. P. Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction. Nature 492: 128-132, 2012. [PubMed: 23135401] [Full Text: https://doi.org/10.1038/nature11590]
Zheng, Q. Y., Yan, D., Ouyang, X. M., Du, L. L., Yu, H., Chang, B., Johnson, K. R., Liu, X. Z. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum. Molec. Genet. 14: 103-111, 2005. [PubMed: 15537665] [Full Text: https://doi.org/10.1093/hmg/ddi010]