Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D

Nat Genet. 2001 Jan;27(1):108-12. doi: 10.1038/83667.

Abstract

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital sensorineural hearing loss, vestibular dysfunction and visual impairment due to early onset retinitis pigmentosa (RP). So far, six loci (USH1A-USH1F) have been mapped, but only two USH1 genes have been identified: MYO7A for USH1B and the gene encoding harmonin for USH1C. We identified a Cuban pedigree linked to the locus for Usher syndrome type 1D (MIM 601067) within the q2 region of chromosome 10). Affected individuals present with congenital deafness and a highly variable degree of retinal degeneration. Using a positional candidate approach, we identified a new member of the cadherin gene superfamily, CDH23. It encodes a protein of 3,354 amino acids with a single transmembrane domain and 27 cadherin repeats. In the Cuban family, we detected two different mutations: a severe course of the retinal disease was observed in individuals homozygous for what is probably a truncating splice-site mutation (c.4488G-->C), whereas mild RP is present in individuals carrying the homozygous missense mutation R1746Q. A variable expression of the retinal phenotype was seen in patients with a combination of both mutations. In addition, we identified two mutations, Delta M1281 and IVS51+5G-->A, in a German USH1 patient. Our data show that different mutations in CDH23 result in USH1D with a variable retinal phenotype. In an accompanying paper, it is shown that mutations in the mouse ortholog cause disorganization of inner ear stereocilia and deafness in the waltzer mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cadherins / chemistry
  • Cadherins / genetics*
  • Cadherins / metabolism
  • Cloning, Molecular
  • Consensus Sequence / genetics
  • Cuba
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Genotype
  • Germany
  • Hearing Loss, Sensorineural / genetics*
  • Humans
  • Male
  • Molecular Sequence Data
  • Multigene Family / genetics*
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • RNA Splice Sites / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Syndrome

Substances

  • CDH23 protein, human
  • Cadherins
  • RNA Splice Sites
  • RNA, Messenger

Associated data

  • GENBANK/AF312024