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

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.

Fruit Flies in Biomedical Research

“…There have been several statistical tools that have been employed to aid in the analysis to prioritize genes and variants (Liu et al 2011;Petrovski et al 2013). Accordingly, understanding rare Mendelian phenotypes relies on extensive functional studies, and the value of model organisms is on the rise (Karaca et al 2014;Santos-Cortez et al 2014;Schaffer et al 2014).…”

Identification of OSBPL2 as a novel candidate gene for progressive nonsyndromic hearing loss by whole-exome sequencing

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] It is estimated that more than 230 novel rare disease genes have been discovered to date using WES. 11 Several new NSHLcausative genes have also recently been revealed via WES, including GPSM2, DNMT1, BDP1, ELMOD3, TNC, GRXCR2, and ADCY1.…”

“…11 Several new NSHLcausative genes have also recently been revealed via WES, including GPSM2, DNMT1, BDP1, ELMOD3, TNC, GRXCR2, and ADCY1. [12][13][14][15][16][17][18] Thus, WES is a powerful approach for investigating the genetic basis of human disease.…”

Using Zebrafish to Study Human Deafness and Hearing Regeneration

“…Morpholino-mediated knockdown of both adcy1a and adcy1b showed curved bodies, smaller eyes and brains. However, more than 90% adcy1a morphants possessed a normal startle response, while only a few adcy1b morphants responded to acoustic stimuli [47] . FM-143 fluorescent dye staining (a simple test of hair cell functionality in live embryos) was not endocytosed into hair cells of adcy1b morphants, while adcy1a morphants incorporated the dye normally, demonstrating that it is the adcy1b gene that is essential for hearing in zebrafish [47] .…”

“…A homozygous mutation in the adenylate cyclase 1 (ADCY1) gene was identified in the members of a Pakistani family with DFNB44 [47] . Adenylate cyclase is involved in the catalysis of ATP to cyclic AMP, an important component in the mechanotransduction of hearing [48] .…”