PUBLICATION

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

Authors
Santos-Cortez, R.L., Lee, K., Giese, A.P., Ansar, M., Amin-Ud-Din, M., Rehn, K., Wang, X., Aziz, A., Chiu, I., Hussain Ali, R., Smith, J.D., Shendure, J., Bamshad, M., Nickerson, D.A., Ahmed, Z.M., Ahmad, W., Riazuddin, S., and Leal, S.M.
ID
ZDB-PUB-140404-14
Date
2014
Source
Human molecular genetics   23(12): 3289-98 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Adenylyl Cyclases/chemistry
  • Adenylyl Cyclases/genetics*
  • Adenylyl Cyclases/metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Codon, Nonsense
  • Cyclic AMP/metabolism*
  • Cytoplasm/metabolism
  • Ear, Inner/growth & development
  • Ear, Inner/metabolism*
  • Female
  • Hair Cells, Auditory/metabolism*
  • Hearing Loss/enzymology
  • Hearing Loss/pathology*
  • Humans
  • Labyrinth Supporting Cells/metabolism
  • Male
  • Mice
  • Zebrafish/genetics
PubMed
24482543 Full text @ Hum. Mol. Genet.
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.

Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes