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. 2016 Feb 4;98(2):331-8.
doi: 10.1016/j.ajhg.2015.12.004. Epub 2016 Jan 21.

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

Regie Lyn P Santos-Cortez  1 , Rabia Faridi  2 , Atteeq U Rehman  3 , Kwanghyuk Lee  1 , Muhammad Ansar  4 , Xin Wang  1 , Robert J Morell  3 , Rivka Isaacson  5 , Inna A Belyantseva  3 , Hang Dai  1 , Anushree Acharya  1 , Tanveer A Qaiser  6 , Dost Muhammad  7 , Rana Amjad Ali  8 , Sulaiman Shams  9 , Muhammad Jawad Hassan  10 , Shaheen Shahzad  11 , Syed Irfan Raza  12 , Zil-E-Huma Bashir  6 , Joshua D Smith  13 , Deborah A Nickerson  13 , Michael J Bamshad  13 ; University of Washington Center for Mendelian Genomics; Sheikh Riazuddin  14 , Wasim Ahmad  12 , Thomas B Friedman  3 , Suzanne M Leal  15
Affiliations

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

Regie Lyn P Santos-Cortez et al. Am J Hum Genet. .

Abstract

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 ∼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.

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Figures

Figure 1
Figure 1
Pedigree Drawings, Mutation Information, and Audiograms for Families with S1PR2 Variants (A) Family DEM4154 with the c.323G>C (p.Arg108Pro) variant. Individuals whose DNA samples were submitted for exome sequencing are marked with asterisks. The mapped interval from linkage analysis and homozygosity mapping lies between D19S1034 and D19S433 (6.11–30.42 Mb). Note that a ZNF91 variant (23.56 Mb) does not segregate with hearing impairment, therefore reducing the mapped interval to 17.45 Mb. (B) Air-conduction audiograms for individuals V-4 of family DEM4154 (solid lines) and IV-1 and IV-3 of family PKDF1400 (arrows denote residual hearing). Red circles, right ear; blue crosses, left ear. Age (years) at audiometry: 4154 V-4, 20; PKDF1400 IV-1, 19; PKDF1400 IV-3, 12. All three individuals have congenital, profound hearing loss across all frequencies. (C) Chromatograms comparing an HI individual who is homozygous for each S1PR2 variant, a heterozygous carrier, and a hearing individual. (D) Family PKDF1400 with the c.419A>G (p.Tyr140Cys) variant and STR haplotype segregating with hearing impairment. The mapped interval from linkage analysis and homozygosity mapping lies between D19S884 and D19S885 (8.15–16.21 Mb), so the length of the mapped interval is 8.06 Mb.
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