Autosomal-Recessive Hearing Impairment Due to Rare Missense Variants within S1PR2
2016; Elsevier BV; Volume: 98; Issue: 2 Linguagem: Inglês
10.1016/j.ajhg.2015.12.004
ISSN1537-6605
AutoresRegie Lyn P. Santos‐Cortez, Rabia Faridi, Atteeq U. Rehman, Kwanghyuk Lee, Muhammad Ansar, Xin Wang, Robert J. Morell, Rivka L. Isaacson, Inna A. Belyantseva, Hang Dai, Anushree Acharya, Tanveer Ahmed Qaiser, Dost Muhammad, Rana Amjad Ali, Sulaiman Shams, Muhammad Jawad Hassan, Shaheen Shahzad, Syed Irfan Raza, Zil-e-Huma Bashir, Joshua D. Smith, Deborah A. Nickerson, Michael J. Bamshad, Sheikh Riazuddin, Wasim Ahmad, Thomas B. Friedman, Suzanne M. Leal,
Tópico(s)Protein Tyrosine Phosphatases
ResumoThe 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. 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. Sphingosine-1-phosphate (S1P) is one of the most studied sphingolipids due to its multiple roles in cellular proliferation, inflammation, migration, cytoskeletal organization, and angiogenesis that are mediated by either intracellular targets (e.g., class-I histone deacetylases) or one of five transmembrane G protein-coupled receptors (GPCRs), namely S1PR1–5.1Adada M. Canals D. Hannun Y.A. Obeid L.M. Sphingosine-1-phosphate receptor 2.FEBS J. 2013; 280: 6354-6366Crossref PubMed Scopus (90) Google Scholar Over the past 20 years, the tissue distribution of these five receptors and the phenotypes of knockout mice for each S1PR have been well documented,1Adada M. Canals D. Hannun Y.A. Obeid L.M. Sphingosine-1-phosphate receptor 2.FEBS J. 2013; 280: 6354-6366Crossref PubMed Scopus (90) Google Scholar such as vascular phenotypes for S1PR1,2Liu Y. Wada R. Yamashita T. Mi Y. Deng C.X. Hobson J.P. Rosenfeldt H.M. Nava V.E. Chae S.S. Lee M.J. et al.Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation.J. Clin. Invest. 2000; 106: 951-961Crossref PubMed Scopus (990) Google Scholar deafness for S1PR2,3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar small litter size for S1PR3,6Ishii I. Friedman B. Ye X. Kawamura S. McGiffert C. Contos J.J. Kingsbury M.A. Zhang G. Brown J.H. Chun J. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3.J. Biol. Chem. 2001; 276: 33697-33704Crossref PubMed Scopus (237) Google Scholar atypical megakaryocytes for S1PR4,7Golfier S. Kondo S. Schulze T. Takeuchi T. Vassileva G. Achtman A.H. Gräler M.H. Abbondanzo S.J. Wiekowski M. Kremmer E. et al.Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine-1-phosphate receptor S1P4.FASEB J. 2010; 24: 4701-4710Crossref PubMed Scopus (65) Google Scholar and lack of peripheral monocytes for S1PR5.8Debien E. Mayol K. Biajoux V. Daussy C. De Aguero M.G. Taillardet M. Dagany N. Brinza L. Henry T. Dubois B. et al.S1PR5 is pivotal for the homeostasis of patrolling monocytes.Eur. J. Immunol. 2013; 43: 1667-1675Crossref PubMed Scopus (41) Google Scholar In humans, pathogenic variants have not been reported for any of the S1PRs. Previously, the autosomal-recessive (ar) hearing impairment (HI) in Pakistani family DEM4154 was mapped to the DFNB68 locus (MIM: 610419) on chromosome 19p13.2 with a statistically significant maximum multipoint LOD score of 4.6 (Figure 1A).9Santos R.L. Hassan M.J. Sikandar S. Lee K. Ali G. Martin Jr., P.E. Wambangco M.A. Ahmad W. Leal S.M. DFNB68, a novel autosomal recessive non-syndromic hearing impairment locus at chromosomal region 19p13.2.Hum. Genet. 2006; 120: 85-92Crossref PubMed Scopus (16) Google Scholar Family DEM4154 segregates both congenital profound HI and limb malformations but no other abnormalities. Audiometric data obtained from hearing-impaired individual V-4 of family DEM4154 showed profound hearing loss at all frequencies (Figure 1B). Within the mapped region lies S1PR2 (MIM: 605111), a gene for which knockout mice and zebrafish models were previously shown to have inner ear structural alterations and hearing loss.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar, 10Hu Z.Y. Zhang Q.Y. Qin W. Tong J.W. Zhao Q. Han Y. Meng J. Zhang J.P. Gene miles-apart is required for formation of otic vesicle and hair cells in zebrafish.Cell Death Dis. 2013; 4: e900Crossref PubMed Scopus (12) Google Scholar Prior to study onset, approval was obtained from the Institutional Review Boards of the Baylor College of Medicine and Affiliated Hospitals, Combined Neuroscience Institutional Review Board at the NIH, National Centre of Excellence in Molecular Biology, University of the Punjab, and Quaid-I-Azam University. Written informed consent was obtained from all family members who participated in the study. For DEM4154, DNA samples of hearing-impaired individuals V-4 and V-7 (Figure 1A) were submitted for exome sequencing at the University of Washington Center for Mendelian Genomics to an average read depth of 77× and 58×, respectively. For both samples, sequence capture was performed in solution with the Roche NimbleGen SeqCap EZ Human Exome Library v.2.0 (∼37 Mb target). Fastq files were aligned to the hg19 human reference sequence using Burrows-Wheeler Aligner (BWA)11Li H. Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform.Bioinformatics. 2009; 25: 1754-1760Crossref PubMed Scopus (26648) Google Scholar to generate demultiplexed BAM files. Realignment of indel regions, recalibration of base qualities, and variant detection and calling were performed using the Genome Analysis Toolkit (GATK)12McKenna A. Hanna M. Banks E. Sivachenko A. Cibulskis K. Kernytsky A. Garimella K. Altshuler D. Gabriel S. Daly M. DePristo M.A. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.Genome Res. 2010; 20: 1297-1303Crossref PubMed Scopus (14776) Google Scholar to produce VCF files. Annotation was performed with SeattleSeq 137. Rare homozygous variants that are shared by the two hearing-impaired individuals and are predicted to be damaging were identified from exome data using information on genotype status, variant quality control (QC), and annotation from RefSeq, SeattleSeq, dbSNP, the Exome Aggregation Consortium (ExAC), and dbNSFP v.2.913Liu X. Jian X. Boerwinkle E. dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations.Hum. Mutat. 2013; 34: E2393-E2402Crossref PubMed Scopus (467) Google Scholar (Table 1). Across the 22 autosomes, only six coding variants were identified to be homozygous in both DEM4154 individuals with HI, passed QC, and had a minor allele frequency (MAF) < 0.01 among South Asian ExAC alleles. All six variants were missense and occurred on chromosome 19, but only three variants occurred within the mapped region and co-segregate with HI (Table 1). Of the three co-segregating variants within 19p13.2, only the c.323G>C (p.Arg108Pro) variant within S1PR2 (Figures 1A and 1C) was not found in dbSNP and ExAC, occurs at a highly conserved residue, and is predicted to be deleterious in all available bioinformatics results (Table 1). For the S1PR2 variant, a maximum two-point LOD score14Fishelson M. Geiger D. Exact genetic linkage computations for general pedigrees.Bioinformatics. 2002; 18: S189-S198Crossref PubMed Scopus (216) Google Scholar of 6.4 was obtained at ϴ = 0. A higher LOD score than in the original mapping of DFNB68 in family DEM4154 was obtained for the S1PR2 variant due to the very low allele frequency of the variant and the inclusion of an additional family member V-6 (Figure 1A) who was born after the family was initially ascertained. Furthermore, Sanger sequencing of the S1PR2 c.323G>C variant in 720 Pakistani control chromosomes and our in-house exome sequence data from 76 unrelated Pakistani individuals with non-HI Mendelian phenotypes were both negative for the S1PR2 variant.Table 1Homozygous Variants on Chromosome 19 from Exome Data of Families DEM4154 and PKDF1400FamilyDEM4154aVariants are homozygous in both hearing-impaired individuals V-4 and V-7 of family DEM4154. For either sample, within the mapped interval overall coverage was 99.4%, with median depth of 45×. Coverage at depth ≥15× was 85%.PKDF1400bVariants are homozygous in both hearing-impaired siblings IV-1 and IV-2 from family PKDF1400. For both PKDF1400 samples, 80%–85% of the mapped interval on chr19 was covered by ≥15×.hg19 Position9,088,37010,335,25913,007,75723,557,52636,558,23538,055,8779,082,63410,335,163Genomic region19p13.219p13.219p13.219p1219q13.1219q13.1219p13.219p13.2Reference alleleTCGGGGTTAlternate alleleGGAAAACCGeneMUC16cAlthough both DEM4154 and PKDF1400 have MUC16 missense variants, these variants have relatively high MAF in South Asian ExAC alleles, occur at non-conserved residues, and are predicted benign by majority of available bioinformatics results. MUC16 variants have been identified previously in probands with other Mendelian phenotypes but have been dismissed as non-causal due to the gene's high polymorphic rate.40S1PR2GCDHdDEM4154 individuals who are homozygous for the GCDH variant do not have signs and symptoms of glutaric aciduria (MIM: 231670). The GCDH variant has relatively high South Asian MAF.ZNF91WDR62ZNF571MUC16cAlthough both DEM4154 and PKDF1400 have MUC16 missense variants, these variants have relatively high MAF in South Asian ExAC alleles, occur at non-conserved residues, and are predicted benign by majority of available bioinformatics results. MUC16 variants have been identified previously in probands with other Mendelian phenotypes but have been dismissed as non-causal due to the gene's high polymorphic rate.40S1PR2MIM606154605111608801603971613583NA606154605111GenBankNM_024690.2NM_004230.3NM_000159.3NM_003430.2NM_173636.4NM_016536.3NM_024690.2NM_004230.3cDNA changec.3445A>Cc.323G>Cc.886G>Ac.71C>Tc.589G>Ac.1453C>Tc.9181A>Gc.419A>GAmino acid changep.Thr1149Prop.Arg108Prop.Gly296Serp.Pro24Leup.Val197Ilep.Arg485Cysp.Met3061Valp.Tyr140CysdbSNP rsID532389640NA539505767NA535488873139005348571388611NANo. ExAC South Asian alleles62 het, 3 hom061 het, 1 hom031 het15 het56 het0ExAC South Asian MAF0.00400.00400.0020.00020.0030ExAC all MAF0.000600.000600.00030.00010.00050MAF in-house exomes (n = 76)000.01300000GERP score−0.45.55.4−0.35.5−1.2−0.55.5phastCons100way_vertebrate01.01.00.0031.0001.0phyloP100way_vertebrate−2.17.89.5−1.59.3−2.0−0.76.0CADD score, scaled0.921.721.30.00228.911.00.00122.9FathmmtoleratedNAdamagingtoleratedtoleratedtoleratedtoleratedtoleratedLikelihood ratio testNAdamagingdamagingNAdamagingNANAdamagingLogistic regression (metaLR)tolerateddamagingdamagingtoleratedtoleratedtoleratedtolerateddamagingMutationAssessornon-functional, neutralfunctional, mediumfunctional, mediumnon-functional, neutralnon-functional, lowfunctional, mediumnon-functional, neutralfunctional, mediumMutationTasterNAdisease-causingdisease-causingpolymorphismdisease-causingpolymorphismpolymorphismdisease-causingPolyPhen2 HVARpossibly damagingprobably damagingprobably damagingbenignprobably damagingbenignbenignprobably damagingPROVEANneutraldeleteriousdeleteriousneutralneutraldeleteriousneutraldeleteriousSIFTdamagingdamagingdamagingtoleratedtoleratedtoleratedtoleratedtoleratedSupport Vector Machine (metaSVM)tolerateddamagingdamagingtoleratedtoleratedtoleratedtolerateddamagingSegregates with phenotypeyesyesyesnononoyesyesAbbreviations are as follows: NA, not available; ExAC, Exome Aggregation Consortium; het, heterozygous; hom, homozygous; MAF, minor allele frequency; CADD, Combined Annotation Dependent Depletion. Conservation scores and bioinformatics results as compiled by dbNSFP v.2.9.a Variants are homozygous in both hearing-impaired individuals V-4 and V-7 of family DEM4154. For either sample, within the mapped interval overall coverage was 99.4%, with median depth of 45×. Coverage at depth ≥15× was 85%.b Variants are homozygous in both hearing-impaired siblings IV-1 and IV-2 from family PKDF1400. For both PKDF1400 samples, 80%–85% of the mapped interval on chr19 was covered by ≥15×.c Although both DEM4154 and PKDF1400 have MUC16 missense variants, these variants have relatively high MAF in South Asian ExAC alleles, occur at non-conserved residues, and are predicted benign by majority of available bioinformatics results. MUC16 variants have been identified previously in probands with other Mendelian phenotypes but have been dismissed as non-causal due to the gene's high polymorphic rate.40Ng S.B. Bigham A.W. Buckingham K.J. Hannibal M.C. McMillin M.J. Gildersleeve H.I. Beck A.E. Tabor H.K. Cooper G.M. Mefford H.C. et al.Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.Nat. Genet. 2010; 42: 790-793Crossref PubMed Scopus (985) Google Scholard DEM4154 individuals who are homozygous for the GCDH variant do not have signs and symptoms of glutaric aciduria (MIM: 231670). The GCDH variant has relatively high South Asian MAF. Open table in a new tab Abbreviations are as follows: NA, not available; ExAC, Exome Aggregation Consortium; het, heterozygous; hom, homozygous; MAF, minor allele frequency; CADD, Combined Annotation Dependent Depletion. Conservation scores and bioinformatics results as compiled by dbNSFP v.2.9. Subsequently, the arHI in another consanguineous family, PKDF1400 (Figure 1D), was mapped to the DFNB68 region. Multipoint linkage analysis using STR marker genotypes revealed a maximum multipoint LOD score of 3.3 on chromosome 19p13.2–p13.12 (Figure 1D). For this family, a second locus was mapped to chromosome 1q23.3–q25.2 with a multipoint LOD score of 2.1 (data not shown). Audiograms for two hearing-impaired individuals of PKDF1400 both show profound hearing loss across all frequencies (Figure 1B). Careful phenotyping of hearing-impaired individuals ruled out any skeletal, immunologic, cardiovascular, or endocrine features. No history of seizures or vestibular defects was detected in any members of family PKDF1400, further supporting the diagnosis of autosomal-recessive nonsyndromic (ARNS) HI. For PKDF1400, sequence capture was performed with the Illumina Nextera Rapid Capture Enrichment Kit to create libraries. DNA samples of hearing-impaired siblings IV-1 and IV-2 were exome sequenced at an average depth of 65× and 77×, respectively. Sequence reads were also mapped against the hg19 human reference sequence using BWA, with recalibration performed using the GATK pipeline. Variant calls were annotated with ANNOVAR. For PKDF1400, within the mapped interval on chromosome 1q23.3–q25.2, no potentially causal variants were identified from exome data. On the other hand, within the mapped interval on chromosome 19p13.2–p13.12, two rare missense variants were shared by the two siblings (Table 1), including S1PR2 c.419A>G (p.Tyr140Cys). Sanger sequencing revealed that the S1PR2 variant segregates with HI in family PKDF1400 (Figures 1C and 1D). The c.419A>G (p.Tyr140Cys) variant occurs at a highly conserved residue, is predicted to be deleterious, and is absent in dbSNP and ExAC, in 720 Pakistani control chromosomes, and in 76 Pakistani exomes with non-HI phenotypes, whereas missense variant c.9181A>G (p.Met3061Val) in MUC16 is present in both ExAC and dbSNP and is predicted to be benign (Table 1). Overall our findings support the contribution of S1PR2 variants to the etiology of ARNSHI in humans. Similar to what we observe in humans, S1pr2−/− mice had profound deafness as early as postnatal day 22.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar The deafness in mice was believed to be degenerative rather than developmental because of the normal appearance of the inner ear prior to establishment of endocochlear potential and onset of hearing at the end of week 2.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar Histologic analysis of the inner ears of knockout mice demonstrated changes within the stria vascularis by postnatal day 14, and degeneration of hair cells and spiral ganglion neurons and overt signs of inner ear dysfunction were obvious by 3 weeks of age.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar Likewise, in the zebrafish morphant in which translation is inhibited for miles-apart, a homolog for S1PR2, lateral line hair cells were absent or shrunken.10Hu Z.Y. Zhang Q.Y. Qin W. Tong J.W. Zhao Q. Han Y. Meng J. Zhang J.P. Gene miles-apart is required for formation of otic vesicle and hair cells in zebrafish.Cell Death Dis. 2013; 4: e900Crossref PubMed Scopus (12) Google Scholar Structural defects were also identified within the otic vesicle, the semicircular canals, otoliths, utricle, and saccule of morphant zebrafish.10Hu Z.Y. Zhang Q.Y. Qin W. Tong J.W. Zhao Q. Han Y. Meng J. Zhang J.P. Gene miles-apart is required for formation of otic vesicle and hair cells in zebrafish.Cell Death Dis. 2013; 4: e900Crossref PubMed Scopus (12) Google Scholar In the S1pr2−/− mouse, progressive deterioration of vestibular epithelium and loss or deformity of utricular and saccular otoconia were evident. The utricular otoconia abnormalities were evident as early as P7 prior to manifestation of behavioral balance abnormalities.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar In contrast, saccular otoconia abnormalities became apparent later during adulthood3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar and correlated well with the behavioral vestibular defects in S1pr2−/− mice as manifested by persistent head tilting and poor swimming ability that became more obvious with age.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar Due to the remote location of families DEM4154 and PKDF1400, reliable documentation by an experienced neurotologist of utricular and saccular function through otolith-ocular reflexes or vestibular evoked myogenic potentials15Manzari L. Burgess A.M. Curthoys I.S. Dissociation between cVEMP and oVEMP responses: different vestibular origins of each VEMP?.Eur. Arch. Otorhinolaryngol. 2010; 267: 1487-1489Crossref PubMed Scopus (33) Google Scholar was not available. On the other hand, affected individuals of both families did not present with obvious vestibular symptoms at any age. The observation of vascular changes in the inner ear prior to cochlear dysfunction is consistent with the role of S1PR2 as a potent regulator of the inflammatory response within vascular endothelium.16Skoura A. Hla T. Regulation of vascular physiology and pathology by the S1P2 receptor subtype.Cardiovasc. Res. 2009; 82: 221-228Crossref PubMed Scopus (86) Google Scholar, 17Zhang W. An J. Jawadi H. Siow D.L. Lee J.F. Zhao J. Gartung A. Maddipati K.R. Honn K.V. Wattenberg B.W. Lee M.J. 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Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar Loss of endocochlear potential, in turn, can lead to deafness and subsequent degeneration of hair cells and spiral ganglion neurons.3MacLennan A.J. Benner S.J. Andringa A. Chaves A.H. Rosing J.L. Vesey R. Karpman A.M. Cronier S.A. Lee N. Erway L.C. Miller M.L. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function.Hear. Res. 2006; 220: 38-48Crossref PubMed Scopus (71) Google Scholar, 4Kono M. Belyantseva I.A. Skoura A. Frolenkov G.I. Starost M.F. Dreier J.L. Lidington D. Bolz S.S. Friedman T.B. Hla T. Proia R.L. Deafness and stria vascularis defects in S1P2 receptor-null mice.J. Biol. Chem. 2007; 282: 10690-10696Crossref PubMed Scopus (157) Google Scholar, 5Herr D.R. Grillet N. Schwander M. Rivera R. Müller U. Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.J. Neurosci. 2007; 27: 1474-1478Crossref PubMed Scopus (103) Google Scholar In vitro, activation of S1PR2 is necessary for phosphorylation of ezrin, radixin, and moesin (ERM) proteins that link actin
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