TY - JOUR

T1 - ADAMTS1, MPDZ, MVD, and SEZ6

T2 - candidate genes for autosomal recessive nonsyndromic hearing impairment

AU - Bharadwaj, Thashi

AU - Schrauwen, Isabelle

AU - Rehman, Sakina

AU - Liaqat, Khurram

AU - Acharya, Anushree

AU - Giese, Arnaud P.J.

AU - Nouel-Saied, Liz M.

AU - Nasir, Abdul

AU - Everard, Jenna L.

AU - Pollock, Lana M.

AU - Zhu, Shaoyuan

AU - Bamshad, Michael J.

AU - Nickerson, Deborah A.

AU - Ali, Raja Hussain

AU - Ullah, Asmat

AU - Wali, Abdul

AU - Ali, Ghazanfar

AU - Santos-Cortez, Regie Lyn P.

AU - Ahmed, Zubair M.

AU - McDermott, Brian M.

AU - Ansar, Muhammad

AU - Riazuddin, Saima

AU - Ahmad, Wasim

AU - Leal, Suzanne M.

N1 - Publisher Copyright: © 2021, The Author(s).

PY - 2022

Y1 - 2022

N2 - Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.

AB - Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.

U2 - 10.1038/s41431-021-00913-x

DO - 10.1038/s41431-021-00913-x

M3 - Journal article

C2 - 34135477

AN - SCOPUS:85108151691

VL - 30

SP - 22

EP - 33

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

ER -