Mutations in Cdh23 , encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D

• Published in: Nature genetics Vol. 27; no. 1; pp. 103 - 107
• Main Authors: Noben-Trauth, Konrad, Palma, Federica Di, Holme, Ralph H, Bryda, Elizabeth C, Belyantseva, Inna A, Pellegrino, Richard, Kachar, Bechara, Steel, Karen P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.01.2001
• Subjects: Amino Acid Sequence; Animals; Auditory Perception - physiology; Base Sequence; Biological and medical sciences; Cadherins - chemistry; Cadherins - genetics; Cadherins - metabolism; Cdh23 gene; Cell differentiation; chromosome 10; Cloning; Cloning, Molecular; Cochlea - metabolism; Complications and side effects; Deafness; DFNB12 gene; Disease Models, Animal; DNA Mutational Analysis; Gene mutations; Genetic aspects; Hair; Hair Cells, Auditory, Inner - metabolism; Hair Cells, Auditory, Inner - pathology; Hair Cells, Auditory, Inner - physiopathology; Hair Cells, Auditory, Inner - ultrastructure; Hearing - physiology; Hearing loss; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Hearing Tests; Identification and classification; In Situ Hybridization; Insects; Kinases; Medical sciences; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Microscopy, Electron, Scanning; Molecular Sequence Data; Mutation; Mutation - genetics; Ophthalmology; otocadherin; Phosphorylation; Proteins; Publishing; Retinopathies; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; RNA, Messenger - analysis; RNA, Messenger - genetics; Syndrome; USH1D gene; Usher's syndrome; United States; United States > US; Retinopathy; Nucleotide sequence; Cell adhesion molecule; Rodentia; Nutrition disorder; Cadherin; Cell differentiation; Gene expression; Genetic disease; Hearing loss; Eye disease; Vertebrata; Mammalia; Mouse; Usher syndrome; Chromosome 10; ENT disease; Mutation
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/83660

Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing loss (Ahl). The human region that is orthologous to the mouse 'waltzer' region is located at 10q21-q22 and contains the human deafness loci DFNB12 and USH1D (refs. 2,3). Numerous mutations at the waltzer locus have been documented causing erratic circling and hearing loss. Here we report the identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes a very large, single-pass transmembrane protein, that we have called otocadherin. It has an extracellular domain that contains 27 repeats; these show significant homology to the cadherin ectodomain. In v6J, a GT transversion creates a premature stop codon. In vAlb, a CT exchange generates an ectopic donor splice site, effecting deletion of 119 nucleotides of exonic sequence. In v2J, a GA transition abolishes the donor splice site, leading to aberrant splice forms. All three alleles are predicted to cause loss of function. We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v2J homozygotes. Our data indicate that otocadherin is a critical component of hair bundle formation. Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D.