Abstract
BackgroundDespite the prevalence of CDH23 mutations in East Asians, its large size hinders investigation. The pathologic mutation p.P240L in CDH23 is common in East Asians. However, whether this mutation represents a common founder or a mutational hot spot is unclear. The prevalence of CDH23 mutations with prelingual severe-to-profound sporadic or autosomal recessive sensorineural hearing loss (arSNHL) is unknown in Koreans.MethodsFrom September 2010 to October 2014, children with severe-to-profound sporadic or arSNHL without phenotypic markers, and their families, were tested for mutations in connexins GJB2, GJB6 and GJB3. Sanger sequencing of CDH23 p.P240L was performed on connexin-negative samples without enlarged vestibular aqueducts (EVA), followed by targeted resequencing of 129 deafness genes, including CDH23, unless p.P240L homozygotes were detected in the first screening. Four p.P240L-allele-linked STR markers were genotyped in 40 normal-hearing control subjects, and the p.P240L carriers in the hearing-impaired cohort, to identify the haplotypes.ResultsFour (3.1 %) of 128 children carried two CDH23 mutant alleles, and SLC26A4 and GJB2 accounted for 18.0 and 17.2 %, respectively. All four children showed profound nonsyndromic SNHL with minimal residual hearing. Interestingly, all had at least one p.P240L mutant allele. Analysis of p.P240L-linked STR markers in these children and other postlingual hearing-impaired adults carrying p.P240L revealed that p.P240L was mainly carried on a single haplotype.Conclusionsp.P240L contributed significantly to Korean pediatric severe arSNHL with a strong founder effect, with implications for future phylogenetic studies. Screening for p.P240L as a first step in GJB2-negative arSNHL Koreans without EVA is recommended.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0624-8) contains supplementary material, which is available to authorized users.
Highlights
Despite the prevalence of CDH23 mutations in East Asians, its large size hinders investigation
This protein is reported to contribute to tip link formation by interacting with protocadherin 15 which is encoded by PCDH15 (NM_001142771)
Our result showed that CDH23 was one of the leading causes of prelingual-onset profound nonsyndromic autosomal recessive sensorineural hearing loss (arSNHL) in children and was a component of the suite of genes that includes SLC26A4 and GJB2, in the Korean pediatric cohort (Fig. 1)
Summary
Despite the prevalence of CDH23 mutations in East Asians, its large size hinders investigation. CDH23 (NM_022124) is a prime example as this gene consists of 69 exons, 11,073 bases, and is located on chromosome 10q21–q22 [4,5,6,7] It encodes cadherin 23, Kim et al J Transl Med (2015) 13:263 consisting of 3,354 amino acids and forms 27 extracellular domains (EC), a single transmembrane domain and a short cytoplasmic domain. Hypo-functional missense mutations result in nonsyndromic hearing loss, preserving retinal and vestibular functions (DFNB12; MIM601386) [5, 10] When these hypofunctional (DFNB12 allele) and nonfunctional mutations (USH1D allele) are in trans configuration to each other, it is presumed that the residual function of the DFNB12 allele preserves vision and the vestibular function, and impacts the function of only hair cells in the inner ear, resulting in the DFNB12 phenotype [11, 12]. More than 50 mutations have been identified in USH1D patients, and over 24 mutations in DFNB12 patients [13]
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