A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential

TY - JOUR

T1 - A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential

AU - Chen, Jing

AU - Lewis, Morag A.

AU - Wai, Alisa

AU - Yin, Lucia

AU - Dawson, Sally J.

AU - Ingham, Neil J.

AU - Steel, Karen P.

N1 - Publisher Copyright: © 2024 The Author(s)

PY - 2024/9/15

Y1 - 2024/9/15

N2 - Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

AB - Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

KW - Endocochlear potential

KW - Progressive hearing loss

KW - Sgms1

KW - Sphingosine-1-phosphate signalling

KW - Stria vascularis

UR - http://www.scopus.com/inward/record.url?scp=85199461684&partnerID=8YFLogxK

U2 - 10.1016/j.heares.2024.109091

DO - 10.1016/j.heares.2024.109091

M3 - Article

C2 - 39067415

AN - SCOPUS:85199461684

SN - 0378-5955

VL - 451

JO - Hearing Research

JF - Hearing Research

M1 - 109091

ER -