Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2

作者：Santos Cortez Regie Lyn P; Faridi Rabia; Rehman Atteeq U; Lee Kwanghyuk; Ansar Muhammad; Wang Xin; Morell Robert J; Isaacson Rivka; Belyantseva Inna A; Dai Hang; Acharya Anushree; Qaiser Tanveer A; Muhammad Dost; Ali Rana Amjad; Shams Sulaiman; Hassan Muhammad Jawad; Shahzad Shaheen; Raza Syed Irfan; Bashir Zil e Huma; Smith Joshua D; Nickerson Deborah A; Bamshad Michael J; Riazuddin Sheikh; Ahmad Wasim; Friedman Thomas B; Leal Suzanne M^*

来源：American Journal of Human Genetics, 2016, 98(2): 331-338.

DOI：10.1016/j.ajhg.2015.12.004

The sphingosine-1-phosphate receptors (S1PRs) are a well-studied class of transmembrane G protein-coupled sphingolipid receptors that mediate multiple cellular processes. However, S1PRs have not been previously reported to be involved in the genetic etiology of human traits. S1PR2 lies within the autosomal-recessive nonsyndromic hearing impairment (ARNSHI) locus DFNB68 on 19p13.2. From exome sequence data we identified two pathogenic S1PR2 variants, c.323G>C (p.Arg108Pro) and c.419A>G (p.Tyr140Cys). Each of these variants co-segregates with congenital profound hearing impairment in consanguineous Pakistani families with maximum LOD scores of 6.4 for family DEM4154 and 3.3 for family PKDF1400. Neither S1PR2 missense variant was reported among similar to 120,000 chromosomes in the Exome Aggregation Consortium database, in 76 unrelated Pakistani exomes, or in 720 Pakistani control chromosomes. Both DNA variants affect highly conserved residues of S1PR2 and are predicted to be damaging by multiple bioinformatics tools. Molecular modeling predicts that these variants affect binding of sphingosine-1-phosphate (p.Arg108Pro) and G protein docking (p.Tyr140Cys). In the previously reported S1pr2(-/-) mice, stria vascularis abnormalities, organ of Corti degeneration, and profound hearing loss were observed. Additionally, hair cell defects were seen in both knockout mice and morphant zebrafish. Family PKDF1400 presents with ARNSHI, which is consistent with the lack of gross malformations in S1pr2(-/-) mice, whereas family DEM4154 has lower limb malformations in addition to hearing loss. Our findings suggest the possibility of developing therapies against hair cell damage (e.g., from ototoxic drugs) through targeted stimulation of S1PR2.

• 出版日期2016-2-4
• 单位NIH