title: Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.
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.
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Regie Lyn P
authors.initials: RL
authors.lastname: Santos-Cortez
authors.affiliation: 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.
authors.forename: Rabia
authors.initials: R
authors.lastname: Faridi
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Atteeq U
authors.initials: AU
authors.lastname: Rehman
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morell
authors.affiliation: Department of Chemistry, Faculty of Natural and Mathematical Sciences, King's College London, London WC2R 2LS, UK.
authors.forename: Rivka
authors.initials: R
authors.lastname: Isaacson
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Inna A
authors.initials: IA
authors.lastname: Belyantseva
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Dai
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Anushree
authors.initials: A
authors.lastname: Acharya
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54550, Pakistan.
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Qaiser
authors.affiliation: Chandka Medical College, Larkana, Sindh 77150, Pakistan.
authors.forename: Dost
authors.initials: D
authors.lastname: Muhammad
authors.affiliation: University of Lahore, Lahore 54550, Pakistan.
authors.forename: Rana Amjad
authors.initials: RA
authors.lastname: Ali
authors.affiliation: Department of Biochemistry, Abdul Wali Khan University, Mardan, 23200 Khyber Pakhtunkhwa, Pakistan.
authors.forename: Sulaiman
authors.initials: S
authors.lastname: Shams
authors.affiliation: Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Science & Technology (NUST), Islamabad 44000, Pakistan.
authors.forename: Muhammad Jawad
authors.initials: MJ
authors.lastname: Hassan
authors.affiliation: Department of Biotechnology and Bioinformatics, International Islamic University, Islamabad 44000, Pakistan.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Shahzad
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Syed Irfan
authors.initials: SI
authors.lastname: Raza
authors.affiliation: Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 54550, Pakistan.
authors.forename: Zil-E-Huma
authors.initials: ZE
authors.lastname: Bashir
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.affiliation: 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.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: sleal@bcm.edu.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005808:Genes, Recessive; D034381:Hearing Loss / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D016015:Logistic Models; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D049349:Receptors, Lysosphingolipid / Q000235:genetics* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine