title: S1PR2 variants associated with auditory function in humans and endocochlear potential decline in mouse.
abstract: Progressive hearing loss is very common in the population but we still know little about the underlying pathology. A new spontaneous mouse mutation (stonedeaf, stdf ) leading to recessive, early-onset progressive hearing loss was detected and exome sequencing revealed a Thr289Arg substitution in Sphingosine-1-Phosphate Receptor-2 (S1pr2). Mutants aged 2 weeks had normal hearing sensitivity, but at 4 weeks most showed variable degrees of hearing impairment, which became severe or profound in all mutants by 14 weeks. Endocochlear potential (EP) was normal at 2 weeks old but was reduced by 4 and 8 weeks old in mutants, and the stria vascularis, which generates the EP, showed degenerative changes. Three independent mouse knockout alleles of S1pr2 have been described previously, but this is the first time that a reduced EP has been reported. Genomic markers close to the human S1PR2 gene were significantly associated with auditory thresholds in the 1958 British Birth Cohort (n = 6099), suggesting involvement of S1P signalling in human hearing loss. The finding of early onset loss of EP gives new mechanistic insight into the disease process and suggests that therapies for humans with hearing loss due to S1P signalling defects need to target strial function.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.|Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Ingham
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Francesca
authors.initials: F
authors.lastname: Carlisle
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Selina
authors.initials: S
authors.lastname: Pearson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.|Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK.
authors.forename: Morag A
authors.initials: MA
authors.lastname: Lewis
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.|Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Buniello
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.|Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
authors.forename: Rivka L
authors.initials: RL
authors.lastname: Isaacson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.|Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pass
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: White
authors.affiliation: UCL Ear Institute, University College London, 332 Gray's Inn Road, London WC1X 8EE, UK.
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Dawson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.|Wolfson Centre for Age-Related Diseases, King's College London, Guys Campus, London, SE1 1UL, UK.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001309:Auditory Threshold; D004195:Disease Models, Animal; D005072:Evoked Potentials, Auditory; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000737:chemistry / Q000235:genetics*; D000081025:Sphingosine-1-Phosphate Receptors; D013316:Stria Vascularis / Q000502:physiology; D000073359:Exome Sequencing
chemical_list: D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C533955:sphingosine-1-phosphate receptor-2, mouse