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.

The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family

“…S1PR2 is part of the sphingosine-1-phosphate signaling (S1P) pathway and is required for normal auditory function [ 9 ]. Detailed expression analysis localized S1pr2 to the cell bodies of inner and outer hair cells, the stria vascularis, spiral ligament fibrocytes, as well as spiral ganglion cells in the mouse [ 9 ].…”

“…S1PR2 is part of the sphingosine-1-phosphate signaling (S1P) pathway and is required for normal auditory function [ 9 ]. Detailed expression analysis localized S1pr2 to the cell bodies of inner and outer hair cells, the stria vascularis, spiral ligament fibrocytes, as well as spiral ganglion cells in the mouse [ 9 ]. S1pr2 defects elicit abnormal endocochlear potential (EP) measurements, morphological changes in the stria vascularis and secondary hair cell degeneration attributed to abnormal EP [ 9 ].…”

“…Detailed expression analysis localized S1pr2 to the cell bodies of inner and outer hair cells, the stria vascularis, spiral ligament fibrocytes, as well as spiral ganglion cells in the mouse [ 9 ]. S1pr2 defects elicit abnormal endocochlear potential (EP) measurements, morphological changes in the stria vascularis and secondary hair cell degeneration attributed to abnormal EP [ 9 ]. To date, one spontaneous missense and three S1pr2 knockout mouse models have been described [ 9 – 12 ].…”

“…S1pr2 defects elicit abnormal endocochlear potential (EP) measurements, morphological changes in the stria vascularis and secondary hair cell degeneration attributed to abnormal EP [ 9 ]. To date, one spontaneous missense and three S1pr2 knockout mouse models have been described [ 9 – 12 ]. All three knockout mouse models showed profound-to-complete deafness at one month of age and progressive vestibular defects [ 10 – 12 ].…”

“…All three knockout mouse models showed profound-to-complete deafness at one month of age and progressive vestibular defects [ 10 – 12 ]. Missense mutants presented rapidly progressive HL with reduced EP followed by a loss of cochlear hair cells [ 9 ]. No other malformations were identified in these mouse models, thus revealing a role of S1pr2 in hearing function without other organ system involvement.…”