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Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9864-8. doi: 10.1073/pnas.1401950111. Epub 2014 Jun 23.

FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing.

Author information

1
Dr. John T. Macdonald Foundation Department of Human Genetics,John P. Hussman Institute for Human Genomics, and.
2
Dr. John T. Macdonald Foundation Department of Human Genetics,John P. Hussman Institute for Human Genomics, andDepartment of Medical Genetics, Erciyes University School of Medicine, Kayseri 38039, Turkey;
3
Departments of Otolaryngology and.
4
Department of Biology, University of Miami, Miami, FL 33146; and.
5
Division of Pediatric Genetics, Ankara University School of Medicine, Ankara 06100, Turkey.
6
Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33136;
7
Dr. John T. Macdonald Foundation Department of Human Genetics,John P. Hussman Institute for Human Genomics, andDivision of Pediatric Genetics, Ankara University School of Medicine, Ankara 06100, Turkey mtekin@med.miami.edu.

Abstract

In a large consanguineous Turkish kindred with recessive nonsyndromic, prelingual, profound hearing loss, we identified in the gene FAM65B (MIM611410) a splice site mutation (c.102-1G>A) that perfectly cosegregates with the phenotype in the family. The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX membrane localization domain. FAM65B is known to be involved in myotube formation and in regulation of cell adhesion, polarization, and migration. We show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear. The wild-type protein targets the plasma membrane, whereas the mutant protein accumulates in cytoplasmic inclusion bodies and does not reach the membrane. In zebrafish, knockdown of fam65b leads to significant reduction of numbers of saccular hair cells and neuromasts and to hearing loss. We conclude that FAM65B is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing.

KEYWORDS:

Mendelian disorder; congenital; deafness; sensorineural; whole-exome sequencing

PMID:
24958875
PMCID:
PMC4103326
DOI:
10.1073/pnas.1401950111
[Indexed for MEDLINE]
Free PMC Article

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