title: Mutations in the calcium-binding motifs of CDH23 and the 35delG mutation in GJB2 cause hearing loss in one family.
abstract: We have ascertained a multi-generation family with apparent autosomal recessive non-syndromic childhood hearing loss (DFNB). Failure to demonstrate linkage in a genome-wide scan with 300 polymorphic markers has suggested genetic heterogeneity for the hearing loss in this family. This heterogeneity could be demonstrated by analysis of candidate loci and genes for DFNB. Patients in one branch of the family (branch C) are homozygous for the 35delG mutation in the GJB2 gene (DFNB1). Patients in two other branches (A and B) carry two new mutations in the cadherin 23 ( CDH23) gene (DFNB12). A homozygous CDH23 c.6442G-->A (D2148N) mutation is present in branch A. Patients in branch B are compound heterozygous for this mutation and the c.4021G-->A (D1341N) mutation. The substituted aspartic acid residues are highly conserved and are part of the calcium-binding sites of the extracellular cadherin (EC) domains. Molecular modeling of the mutated EC domains of CDH23 based on the structure of E-cadherin indicates that calcium-binding is impaired. In addition, other aspartic and glutamic acid residue substitutions in the highly conserved calcium-binding sites reported to cause DFNB12 are also likely to result in a decreased affinity for calcium. Since calcium provides rigidity to the elongated structure of cadherin molecules enabling homophilic lateral interaction, these mutations are likely to impair interactions of CDH23 molecules either with CDH23 or with other proteins. DFNB12 is the first human disorder that can be attributed to inherited missense mutations in the highly conserved residues of the extracellular calcium-binding domain of a cadherin.
authors.affiliation: Department of Otorhinolaryngology, University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Ronald J E
authors.initials: RJ
authors.lastname: Pennings
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Roeters
authors.forename: Peter
authors.initials: P
authors.lastname: Van Hauwe
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Astuto
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Patrick L M
authors.initials: PL
authors.lastname: Huygen
authors.forename: Bellinda
authors.initials: B
authors.lastname: van den Helm
authors.forename: August F
authors.initials: AF
authors.lastname: Deutman
authors.forename: Julie M
authors.initials: JM
authors.lastname: Bork
authors.forename: William J
authors.initials: WJ
authors.lastname: Kimberling
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Cor W R J
authors.initials: CW
authors.lastname: Cremers
authors.forename: Hannie
authors.initials: H
authors.lastname: Kremer
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003241:Consanguinity; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014724:Vestibular Function Tests
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D017630:Connexins; D017931:DNA Primers; C000607042:GJB2 protein, human; D000072259:Connexin 26; D002118:Calcium