S1PR2 variants associated with auditory function in humans and endocochlear potential decline in mouse

Area of Science:

• Genetics
• Neuroscience
• Otolaryngology

Background:

• Progressive hearing loss is a common condition with poorly understood underlying pathology.
• The role of Sphingosine-1-Phosphate Receptor-2 (S1pr2) in auditory function is not fully elucidated.

Purpose of the Study:

• To investigate the genetic basis and pathological mechanisms of a novel spontaneous mouse mutation causing progressive hearing loss.
• To explore the role of S1pr2 in the development and maintenance of hearing.

Main Methods:

• Exome sequencing to identify the causative mutation in the stonedeaf (stdf) mouse.
• Auditory testing and electrophysiological measurements (endocochlear potential) at various ages.
• Histological examination of the stria vascularis.
• Genetic association study in the 1958 British Birth Cohort.

Main Results:

• A Thr289Arg substitution in S1pr2 was identified as the cause of the stdf mutation.
• stdf mice exhibited early-onset progressive hearing loss, starting at 4 weeks and becoming profound by 14 weeks.
• Reduced endocochlear potential and degenerative changes in the stria vascularis were observed in stdf mutants.
• Genomic markers near human S1PR2 were associated with auditory thresholds in a large human cohort.

Conclusions:

• S1pr2 plays a critical role in maintaining hearing, particularly in the function of the stria vascularis and endocochlear potential.
• This study provides new mechanistic insights into progressive hearing loss associated with S1P signaling defects.
• Targeting strial function may be a therapeutic strategy for human hearing loss linked to S1P signaling.