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

TitleAutosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2.
Publication TypeJournal Article
Year of Publication2016
AuthorsSantos-Cortez, RLyn P, Faridi, R, Rehman, AU, Lee, K, Ansar, M, Wang, X, Morell, RJ, Isaacson, R, Belyantseva, IA, Dai, H, Acharya, A, Qaiser, TA, Muhammad, D, Ali, RAmjad, Shams, S, Hassan, MJawad, Shahzad, S, Raza, SIrfan, Bashir, Z-E-H, Smith, JD, Nickerson, DA, Bamshad, MJ, Riazuddin, S, Ahmad, W, Friedman, TB, Leal, SM
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2016 Feb 04
KeywordsAmino Acid Sequence, Asian Continental Ancestry Group, Chromosomes, Human, Pair 19, Exome, Genes, Recessive, Hearing Loss, Humans, Lod Score, Logistic Models, Lysophospholipids, Models, Molecular, Molecular Sequence Data, Mutation, Missense, Pedigree, Phenotype, Receptors, Lysosphingolipid, Sphingosine

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID26805784
PubMed Central IDPMC4746333
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
N01HG65403 / HG / NHGRI NIH HHS / United States
R01 DC011651 / DC / NIDCD NIH HHS / United States
Z01 DC000039 / DC / NIDCD NIH HHS / United States
R01 DC003594 / DC / NIDCD NIH HHS / United States
U54HG006493 / HG / NHGRI NIH HHS / United States
/ / Intramural NIH HHS / United States
DC000039-18 / DC / NIDCD NIH HHS / United States
T32 DC000039 / DC / NIDCD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States