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Hum Mol Genet. 2014 Jun 15;23(12):3289-98. doi: 10.1093/hmg/ddu042. Epub 2014 Jan 29.

Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish.

Author information

1
Department of Molecular and Human Genetics, Center for Statistical Genetics and.
2
Division of Pediatric Ophthalmology and Division of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45221, USA.
3
Department of Molecular and Human Genetics, Center for Statistical Genetics and Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
4
Dera Ghazi Khan Campus, University of Education, Lahore 32200, Pakistan and.
5
Division of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45221, USA.
6
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
7
Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
8
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
9
Division of Pediatric Ophthalmology and.
10
Department of Molecular and Human Genetics, Center for Statistical Genetics and sleal@bcm.edu.

Abstract

Cyclic AMP (cAMP) production, which is important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearing-impaired family members, a nonsense mutation c.3112C>T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individuals who are homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1 has an evolutionarily conserved role in hearing and that cAMP signaling is important to hair cell function within the inner ear.

PMID:
24482543
PMCID:
PMC4030782
DOI:
10.1093/hmg/ddu042
[Indexed for MEDLINE]
Free PMC Article

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