title: Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D.
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.
authors.affiliation: Institut für Humangenetik, UniversitätsKlinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bolz
authors.forename: B
authors.initials: B
authors.lastname: von Brederlow
authors.forename: A
authors.initials: A
authors.lastname: Ramírez
authors.forename: E C
authors.initials: EC
authors.lastname: Bryda
authors.forename: K
authors.initials: K
authors.lastname: Kutsche
authors.forename: H G
authors.initials: HG
authors.lastname: Nothwang
authors.forename: M
authors.initials: M
authors.lastname: Seeliger
authors.forename: M
authors.initials: M
authors.lastname: del C-Salcedó Cabrera
authors.forename: M C
authors.initials: MC
authors.lastname: Vila
authors.forename: O P
authors.initials: OP
authors.lastname: Molina
authors.forename: A
authors.initials: A
authors.lastname: Gal
authors.forename: C
authors.initials: C
authors.lastname: Kubisch
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D016384:Consensus Sequence / Q000235:genetics; D003462:Cuba; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D005858:Germany; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D022821:RNA Splice Sites; D012333:RNA, Messenger