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

Am J Hum Genet. 2016 Feb 4;98(2):331-8. doi: 10.1016/j.ajhg.2015.12.004.

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

1 Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
2 Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA; Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54550, Pakistan.
3 Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
4 Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
5 Department of Chemistry, Faculty of Natural and Mathematical Sciences, King's College London, London WC2R 2LS, UK.
6 Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54550, Pakistan.
7 Chandka Medical College, Larkana, Sindh 77150, Pakistan.
8 University of Lahore, Lahore 54550, Pakistan.
9 Department of Biochemistry, Abdul Wali Khan University, Mardan, 23200 Khyber Pakhtunkhwa, Pakistan.
10 Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science & Technology (NUST), Islamabad 44000, Pakistan.
11 Department of Biotechnology and Bioinformatics, International Islamic University, Islamabad 44000, Pakistan.
12 Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
13 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
14 University of Lahore, Lahore 54550, Pakistan; Allama Iqbal Medical Research Centre, Jinnah Hospital Complex, Lahore 54550, Pakistan; Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan.
15 Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].

PMID: 26805784 DOI: 10.1016/j.ajhg.2015.12.004

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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