The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: Evidence from a consanguineous Iranian family

Hofrichter, M. A. H. and Mojarad, M. and Doll, J. and Grimm, C. and Eslahi, A. and Hosseini, N. S. and Rajati, M. and Müller, T. and Dittrich, M. and Maroofian, R. and Haaf, T. and Vona, B. (2018) The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: Evidence from a consanguineous Iranian family. BMC Medical Genetics, 19 (1).

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The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing Evidence from a consanguineous Iranian family.pdf

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Background: Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family. Methods: Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed. Results: The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change. Conclusion: In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss. © 2018 The Author(s).

Item Type: Article
Additional Information: Export Date: 16 February 2020 CODEN: BMGMA Correspondence Address: Vona, B.; Julius Maximilians University, Institute of Human GeneticsGermany; email:
Uncontrolled Keywords: 3D modeling Autosomal recessive non-syndromic hearing loss DFNB68 Mixed hearing loss S1PR2 Whole exome sequencing cysteine guanine arginine protein binding S1PR2 protein, human sphingosine 1 phosphate receptor amino acid substitution Article consanguinity gene segregation genetic association genetic variability hearing impairment homozygosity human Iranian (citizen) mutational analysis Pakistani pathogenesis receptor binding S1PR2 gene sequence homology adolescent chemistry female genetics Iran male metabolism molecular model pedigree procedures Hearing Loss Humans Models, Molecular Receptors, Lysosphingolipid
Subjects: WV Otolaryngology
QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: lib2 lib2 lib2
Date Deposited: 18 May 2020 07:48
Last Modified: 18 May 2020 07:48

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