Abstract
Mutations of PCDH15, encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or nonsyndromic deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3–11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating nonsyndromic deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F, which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15, mutations in the introns or regulatory elements of PCDH15, or an additional locus for type I USH at chromosome 10q21.1.
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Acknowledgments
The authors are grateful to the families who made this research possible. We thank Barbara Ploplis and Nicholas Kusnezov for their technical support. We also thank Julie Schultz, Karen Friderici and Anne Madeo for suggestions regarding this manuscript. This study was supported by the Higher Education Commission, Islamabad, Pakistan; Ministry of Science and Technology, Islamabad, Pakistan and by intramural funds to TBF from the National Institute on Deafness and Other Communication Disorders, NIH (1 ZO1 DC000039-11).
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439_2008_543_Fig5_ESM.jpg
Supplemental Fig. 1 ClustalW alignment of deduced amino acid sequences of human protocadherin-15-CD1 (accession no. AY029237) and orthologs. Amino acids identical or similar to protocadherin-15-CD1 for two or more of the five orthologous genes are indicated by dark grey and light grey boxes. Comparison of the amino-acid sequences of human and mouse CD1 cytoplasmic domains reveals 55% identity and 67% similarity (JPG 1073 kb)
439_2008_543_Fig6_ESM.jpg
Supplemental Fig. 2 ClustalW alignment of deduced amino acid sequences of human protocadherin-15-CD2 (accession no. EU718480) and orthologs. Amino acids identical or similar to protocadherin-15-CD2 for two or more of the five orthologous genes are indicated by dark grey and light grey boxes. Comparison of the amino-acid sequences of human and mouse CD2 cytoplasmic domains reveals 83% identity and 91% similarity (JPG 924 kb)
439_2008_543_Fig7_ESM.jpg
Supplemental Fig. 3 ClustalW alignment of deduced amino acid sequences of human protocadherin-15-CD3 (accession no. EU718482) and orthologs. Amino acids identical or similar to protocadherin-15-CD3 for two or more of the five orthologous genes are indicated by dark grey and light grey boxes. Comparison of the amino-acid sequences of human and mouse CD3 cytoplasmic domains reveals 77% identity and 84% similarity (JPG 551 kb)
439_2008_543_MOESM2_ESM.doc
Supplementary Table 2 Summary of all reported PCDH15 mutations associated with type I USH or nonsyndromic deafness DFNB23 (DOC 128 kb)
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Ahmed, Z.M., Riazuddin, S., Aye, S. et al. Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome. Hum Genet 124, 215–223 (2008). https://doi.org/10.1007/s00439-008-0543-3
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DOI: https://doi.org/10.1007/s00439-008-0543-3