Digenic inheritance of deafness caused by 8J allele of myosin-VIIA and mutations in other Usher I genes

Qing Yin Zheng, John D. Scarborough, Ye Zheng, Heping Yu, Dongseok Choi, Peter G. Gillespie

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Inherited hearing loss in mice has contributed substantially to our understanding of inner-ear function. We identified a new allele at the Myo7a locus, Myo7ash1-8J; genomic characterization indicated that Myo7ash1-8J arose from complex deletion encompassing exons 38-40 and 42-46. Homozygous mutant mice had no detectable auditory brainstem response, displayed highly disorganized hair-cell stereocilia and had no detectable MYO7A protein. We generated mice that were digenic heterozygotes for Myo7ash1-8J and one of each Cdh23v-2J, Ush1gjs or Pcdh15av-3J alleles, or an Ush1c null allele. Significant levels of age-related hearing loss were detected in +/Myo7ash1-8J +/Ush1gjs, +/Myo7ash1-8J +/Cdh23v-2J and +/Myo7ash1-8J +/Pcdh15av-3Jdouble heterozygous micecompared with age-matched single heterozygous animals, suggesting epistasis between Myo7a and each of the three loci. +/Pcdh15av-3J +/Ush1gjs double heterozygous mice also showed elevated hearing loss, suggesting Pcdh15-Ush1g epistasis. While we readily detected MYO7A, USH1C, CDH23 and PCDH15 using mass spectrometry of purified chick utricle hair bundles, we did not detect USH1G. Consistent with that observation, Ush1g microarray signals were much lower in chick cochlea than those of Myo7a, Ush1c, Cdh23 and Pcdh15 and were not detected in the chick utricle. These experiments confirm the importance of MYO7A for the development and maintenance of bundle function and support the suggestion that MYO7A, USH1G (Sans) and CDH23 form the upper tip-link complex in adult mice, likely in combination with USH1C (harmonin). MYO7A, USH1G and PCDH15 may form another complex in stereocilia. USH1G may be a limiting factor in both complexes.

Original languageEnglish (US)
Article numberdds084
Pages (from-to)2588-2598
Number of pages11
JournalHuman molecular genetics
Issue number11
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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