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

Regie Lyn P. Santos-Cortez, Kwanghyuk Lee, Arnaud P. Giese, Muhammad Ansar, Muhammad Amin-Ud-Din, Kira Rehn, Xin Wang, Abdul Aziz, Ilene Chiu, Raja Hussain Ali, Joshua D. Smith, Jay Shendure, Michael Bamshad, Deborah A. Nickerson, Zubair M. Ahmed, Wasim Ahmad, Saima Riazuddin, Suzanne M. Leal

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

CyclicAMP(cAMP) production, whichis 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 wasmapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearingimpaired 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. Individualswhoare homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafishadcy1bmorphantshadnoFM1-43dyeuptakeandlacked 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 ADCY1has an evolutionarily conserved role in hearing and thatcAMP signaling is important to hair cell function within the inner ear

Original languageEnglish (US)
Pages (from-to)3289-3298
Number of pages10
JournalHuman Molecular Genetics
Volume23
Issue number12
DOIs
StatePublished - Jan 1 2014

Fingerprint

Zebrafish
Hearing Loss
Adenylyl Cyclases
Hearing
Inner Ear
Mutation
Tail
Startle Reflex
Auditory Hair Cells
Stereocilia
Exome
Nonsense Codon
COS Cells
Pakistan
Cochlea
Calmodulin
Microvilli
Cell Nucleus
DNA Sequence Analysis
Actins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Santos-Cortez, R. L. P., Lee, K., Giese, A. P., Ansar, M., Amin-Ud-Din, M., Rehn, K., ... Leal, S. M. (2014). Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. Human Molecular Genetics, 23(12), 3289-3298. https://doi.org/10.1093/hmg/ddu042

Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. / Santos-Cortez, Regie Lyn P.; Lee, Kwanghyuk; Giese, Arnaud P.; Ansar, Muhammad; Amin-Ud-Din, Muhammad; Rehn, Kira; Wang, Xin; Aziz, Abdul; Chiu, Ilene; Ali, Raja Hussain; Smith, Joshua D.; Shendure, Jay; Bamshad, Michael; Nickerson, Deborah A.; Ahmed, Zubair M.; Ahmad, Wasim; Riazuddin, Saima; Leal, Suzanne M.

In: Human Molecular Genetics, Vol. 23, No. 12, 01.01.2014, p. 3289-3298.

Research output: Contribution to journalArticle

Santos-Cortez, RLP, Lee, K, Giese, AP, Ansar, M, Amin-Ud-Din, M, Rehn, K, Wang, X, Aziz, A, Chiu, I, Ali, RH, Smith, JD, Shendure, J, Bamshad, M, Nickerson, DA, Ahmed, ZM, Ahmad, W, Riazuddin, S & Leal, SM 2014, 'Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish', Human Molecular Genetics, vol. 23, no. 12, pp. 3289-3298. https://doi.org/10.1093/hmg/ddu042
Santos-Cortez, Regie Lyn P. ; Lee, Kwanghyuk ; Giese, Arnaud P. ; Ansar, Muhammad ; Amin-Ud-Din, Muhammad ; Rehn, Kira ; Wang, Xin ; Aziz, Abdul ; Chiu, Ilene ; Ali, Raja Hussain ; Smith, Joshua D. ; Shendure, Jay ; Bamshad, Michael ; Nickerson, Deborah A. ; Ahmed, Zubair M. ; Ahmad, Wasim ; Riazuddin, Saima ; Leal, Suzanne M. / Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 12. pp. 3289-3298.
@article{4f81b92971d24b6abe934825baadb2f1,
title = "Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish",
abstract = "CyclicAMP(cAMP) production, whichis 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 wasmapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearingimpaired 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. Individualswhoare homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafishadcy1bmorphantshadnoFM1-43dyeuptakeandlacked 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 ADCY1has an evolutionarily conserved role in hearing and thatcAMP signaling is important to hair cell function within the inner ear",
author = "Santos-Cortez, {Regie Lyn P.} and Kwanghyuk Lee and Giese, {Arnaud P.} and Muhammad Ansar and Muhammad Amin-Ud-Din and Kira Rehn and Xin Wang and Abdul Aziz and Ilene Chiu and Ali, {Raja Hussain} and Smith, {Joshua D.} and Jay Shendure and Michael Bamshad and Nickerson, {Deborah A.} and Ahmed, {Zubair M.} and Wasim Ahmad and Saima Riazuddin and Leal, {Suzanne M.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1093/hmg/ddu042",
language = "English (US)",
volume = "23",
pages = "3289--3298",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish

AU - Santos-Cortez, Regie Lyn P.

AU - Lee, Kwanghyuk

AU - Giese, Arnaud P.

AU - Ansar, Muhammad

AU - Amin-Ud-Din, Muhammad

AU - Rehn, Kira

AU - Wang, Xin

AU - Aziz, Abdul

AU - Chiu, Ilene

AU - Ali, Raja Hussain

AU - Smith, Joshua D.

AU - Shendure, Jay

AU - Bamshad, Michael

AU - Nickerson, Deborah A.

AU - Ahmed, Zubair M.

AU - Ahmad, Wasim

AU - Riazuddin, Saima

AU - Leal, Suzanne M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - CyclicAMP(cAMP) production, whichis 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 wasmapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearingimpaired 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. Individualswhoare homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafishadcy1bmorphantshadnoFM1-43dyeuptakeandlacked 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 ADCY1has an evolutionarily conserved role in hearing and thatcAMP signaling is important to hair cell function within the inner ear

AB - CyclicAMP(cAMP) production, whichis 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 wasmapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearingimpaired 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. Individualswhoare homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafishadcy1bmorphantshadnoFM1-43dyeuptakeandlacked 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 ADCY1has an evolutionarily conserved role in hearing and thatcAMP signaling is important to hair cell function within the inner ear

UR - http://www.scopus.com/inward/record.url?scp=84901316993&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901316993&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu042

DO - 10.1093/hmg/ddu042

M3 - Article

VL - 23

SP - 3289

EP - 3298

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 12

ER -