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Mouse models of USH1C and DFNB18: phenotypic and molecular analyses of two new spontaneous mutations of the Ush1c gene.

We mapped two new recessive mutations causing circling behavior and deafness to the same region on chromosome 7 and showed they are allelic by complementation analysis. One was named 'deaf circler' (allele symbol dfcr) and the other 'deaf circler 2 Jackson' (allele symbol dfcr-2J). Both were shown to be mutations of the Ush1c gene, the mouse ortholog of the gene responsible for human Usher syndrome type IC and for the non-syndromic deafness disorder DFNB18. The Ush1c gene contains 28 exons, 20 that are constitutive and eight that are alternatively spliced. The dfcr mutation is a 12.8 kb intragenic deletion that eliminates three constitutive and five alternatively spliced exons. The dfcr-2J mutation is a 1 bp deletion in an alternatively spliced exon that creates a transcriptional frame shift, changing 38 amino acid codons before introducing a premature stop codon. Both mutations cause congenital deafness and severe balance deficits due to inner ear dysfunction. The stereocilia of cochlear hair cells are disorganized and splayed in mutant mice, with subsequent degeneration of the hair cells and spiral ganglion cells. Harmonin, the protein encoded by Ush1c, has been shown to bind, by means of its PDZ-domains, with the products of other Usher syndrome genes, including Myo7a, Cdh23 and Sans. The complexes formed by these protein interactions are thought to be essential for maintaining the integrity of hair cell stereocilia. The Ush1c mutant mice described here provide a means to directly investigate these interactions in vivo and to evaluate gene structure-function relationships that affect inner ear and eye phenotypes.

Pubmed ID: 14519688

Authors

  • Johnson KR
  • Gagnon LH
  • Webb LS
  • Peters LL
  • Hawes NL
  • Chang B
  • Zheng QY

Journal

Human molecular genetics

Publication Data

December 1, 2003

Associated Grants

  • Agency: NCI NIH HHS, Id: CA34196
  • Agency: NIDCD NIH HHS, Id: DC04301
  • Agency: NIDCD NIH HHS, Id: DC04376
  • Agency: NIDCD NIH HHS, Id: DC62108
  • Agency: NIDDK NIH HHS, Id: DK07449
  • Agency: NEI NIH HHS, Id: EY07758
  • Agency: NHLBI NIH HHS, Id: HL64885
  • Agency: NCI NIH HHS, Id: P30 CA034196-259007
  • Agency: NCRR NIH HHS, Id: P40 RR001183-24
  • Agency: NIDCD NIH HHS, Id: R01 DC004301
  • Agency: NIDCD NIH HHS, Id: R01 DC004301-02
  • Agency: NEI NIH HHS, Id: R01 EY007758
  • Agency: NEI NIH HHS, Id: R01 EY007758-20
  • Agency: NHLBI NIH HHS, Id: R01 HL064885
  • Agency: NHLBI NIH HHS, Id: R01 HL064885-04
  • Agency: NIDCD NIH HHS, Id: R03 DC004376
  • Agency: NIDCD NIH HHS, Id: R03 DC004376-01A1
  • Agency: NIDCD NIH HHS, Id: R03 DC004376-02
  • Agency: NIDCD NIH HHS, Id: R03 DC004376-03
  • Agency: NIDCD NIH HHS, Id: R21 DC005846
  • Agency: NIDCD NIH HHS, Id: R21 DC005846-01A1
  • Agency: NCRR NIH HHS, Id: RR01183

Mesh Terms

  • Animals
  • Base Sequence
  • Carrier Proteins
  • Chromosome Mapping
  • Cochlea
  • Deafness
  • Eye
  • Genes, Recessive
  • Genetic Complementation Test
  • Hair Cells, Auditory, Inner
  • Mice
  • Mutation
  • Phenotype
  • Protein Biosynthesis
  • Transcription, Genetic