Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish.
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.
Department of Molecular and Human Genetics, Center for Statistical Genetics and.
Regie Lyn P
RL
Santos-Cortez
Department of Molecular and Human Genetics, Center for Statistical Genetics and.
Kwanghyuk
K
Lee
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.
Arnaud P
AP
Giese
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.
Muhammad
M
Ansar
Dera Ghazi Khan Campus, University of Education, Lahore 32200, Pakistan and.
Muhammad
M
Amin-Ud-Din
Division of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45221, USA.
Kira
K
Rehn
Department of Molecular and Human Genetics, Center for Statistical Genetics and.
Xin
X
Wang
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Abdul
A
Aziz
Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Ilene
I
Chiu
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Raja
R
Hussain Ali
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Joshua D
JD
Smith
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Jay
J
Shendure
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Michael
M
Bamshad
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Deborah A
DA
Nickerson
Division of Pediatric Ophthalmology and.
Zubair M
ZM
Ahmed
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Wasim
W
Ahmad
Division of Pediatric Otolaryngology-Head and Neck Surgery, Cincinnati Children's Hospital Research Foundation, University of Cincinnati, Cincinnati, OH 45221, USA.
Saima
S
Riazuddin
Department of Molecular and Human Genetics, Center for Statistical Genetics and sleal@bcm.edu.
Suzanne M
SM
Leal
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018389:Codon, Nonsense; D000242:Cyclic AMP / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D007758:Ear, Inner / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D006198:Hair Cells, Auditory / Q000378:metabolism*; D034381:Hearing Loss / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007760:Labyrinth Supporting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D015027:Zebrafish / Q000235:genetics
D018389:Codon, Nonsense; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1