Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment.

Autor: Adadey SM; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana.; Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa., Schrauwen I; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Centre, New York, NY, USA., Aboagye ET; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana., Bharadwaj T; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Centre, New York, NY, USA., Esoh KK; Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa., Basit S; Center for Genetics and Inherited Diseases, Taibah University Al Madinah Al Munawarah, Al Munawarah, Saudi Arabia., Acharya A; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Centre, New York, NY, USA., Nouel-Saied LM; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Centre, New York, NY, USA., Liaqat K; Faculty of Biological Sciences, Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan., Wonkam-Tingang E; Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa., Mowla S; Division of Haematology, Faculty of Health Sciences, Department of Pathology, University of Cape Town, Cape Town, South Africa., Awandare GA; West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Accra, Ghana., Ahmad W; Faculty of Biological Sciences, Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan., Leal SM; Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Centre, New York, NY, USA. sml3@cumc.columbia.edu.; Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Centre, New York, NY, USA. sml3@cumc.columbia.edu., Wonkam A; Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. ambroise.wonkam@uct.ac.za.
Jazyk: angličtina
Zdroj: Journal of human genetics [J Hum Genet] 2021 Dec; Vol. 66 (12), pp. 1169-1175. Date of Electronic Publication: 2021 Jul 05.
DOI: 10.1038/s10038-021-00954-6
Abstrakt: Congenital hearing impairment (HI) is genetically heterogeneous making its genetic diagnosis challenging. Investigation of novel HI genes and variants will enhance our understanding of the molecular mechanisms and to aid genetic diagnosis. We performed exome sequencing and analysis using DNA samples from affected members of two large families from Ghana and Pakistan, segregating autosomal-dominant (AD) non-syndromic HI (NSHI). Using in silico approaches, we modeled and evaluated the effect of the likely pathogenic variants on protein structure and function. We identified two likely pathogenic variants in SLC12A2, c.2935G>A:p.(E979K) and c.2939A>T:p.(E980V), which segregate with NSHI in a Ghanaian and Pakistani family, respectively. SLC12A2 encodes an ion transporter crucial in the homeostasis of the inner ear endolymph and has recently been reported to be implicated in syndromic and non-syndromic HI. Both variants were mapped to alternatively spliced exon 21 of the SLC12A2 gene. Exon 21 encodes for 17 residues in the cytoplasmatic tail of SLC12A2, is highly conserved between species, and preferentially expressed in cochlear tissues. A review of previous studies and our current data showed that out of ten families with either AD non-syndromic or syndromic HI, eight (80%) had variants within the 17 amino acid residue region of exon 21 (48 bp), suggesting that this alternate domain is critical to the transporter activity in the inner ear. The genotypic spectrum of SLC12A2 was expanded and the involvement of SLC12A2 in ADNSHI was confirmed. These results also demonstrate the role that SLC12A2 plays in ADNSHI in diverse populations including sub-Saharan Africans.
(© 2021. The Author(s).)
Databáze: MEDLINE
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