Further confirmation of the association of SLC12A2 with non-syndromic autosomal-dominant hearing impairment
Autor: | Thashi Bharadwaj, Anushree Acharya, Khurram Liaqat, Gordon A. Awandare, Kevin K Esoh, Elvis Twumasi Aboagye, Shaheen Mowla, Suzanne M. Leal, Sulman Basit, Isabelle Schrauwen, Samuel Mawuli Adadey, Edmond Wonkam-Tingang, Liz M Nouel-Saied, Wasim Ahmad, Ambroise Wonkam |
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Rok vydání: | 2021 |
Předmět: |
Male
Models Molecular Genotype In silico Biology Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Exon 0302 clinical medicine Exome Sequencing Genetics medicine Humans Solute Carrier Family 12 Member 2 Genetic Predisposition to Disease Inner ear Amino Acid Sequence Hearing Loss Gene Alleles Genetic Association Studies Genetics (clinical) Exome sequencing 030304 developmental biology 0303 health sciences Disease genetics Genetic heterogeneity Sequence Analysis DNA Pedigree Phenotype medicine.anatomical_structure chemistry Mutation Female Neurological disorders 030217 neurology & neurosurgery DNA |
Zdroj: | Journal of Human Genetics |
ISSN: | 1435-232X 1434-5161 |
Popis: | 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. |
Databáze: | OpenAIRE |
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