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A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice

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Abstract

Inbred mouse strains serve as important models for human presbycusis or age-related hearing loss. We previously mapped a locus (ahl8) contributing to the progressive hearing loss of DBA/2J (D2) mice and later showed that a missense variant of the Fscn2 gene, unique to the D2 inbred strain, was responsible for the ahl8 effect. Although ahl8 can explain much of the hearing loss difference between C57BL/6J (B6) and D2 strain mice, other loci also contribute. Here, we present results of our linkage analyses to map quantitative trait loci (QTLs) that modify the severity of hearing loss associated with the D2 strain Fscn2 ahl8 allele. We searched for modifier loci by analyzing 31 BXD recombinant inbred (RI) lines fixed for the predisposing D2-derived Fscn2 ahl8/ahl8 genotype and found a statistically significant linkage association of threshold means with a QTL on Chr 5, which we designated M5ahl8. The highest association (LOD 4.6) was with markers at the 84–90 Mb position of Chr 5, which could explain about 46 % of the among-RI strain variation in auditory brainstem response (ABR) threshold means. The semidominant nature of the modifying effect of M5ahl8 on the Fscn2 ahl8/ahl8 phenotype was demonstrated by analysis of a backcross involving D2 and B6.D2-Chr11D/LusJ strain mice. The Chr 5 map position of M5ahl8 and the D2 origin of its susceptibility allele correspond to Tmc1m4, a previously reported QTL that modifies outer hair cell degeneration in Tmc1 Bth mutant mice, suggesting that M5ahl8 and Tmc1m4 may represent the same gene affecting maintenance of stereocilia structure and function during aging.

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Acknowledgments

We thank Sandra Gray for her skilled mouse colony management and assistance in the development of the congenic strains. We also thank personnel of the Jackson Laboratory’s Genetic Resource Science Repository for providing us with retired breeder mice from the BXD RI strains. This research was supported by R01 Grant DC005827 (KRJ) from the National Institutes of Health (NIH) and National Institute on Deafness and Other Communication Disorders (NIDCD). The Jackson Laboratory institutional shared services are supported by NIH National Cancer Institute Support Grant CA34196.

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  1. The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    Kenneth R. Johnson, Chantal M. Longo-Guess & Leona H. Gagnon

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  1. Kenneth R. Johnson
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  2. Chantal M. Longo-Guess
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  3. Leona H. Gagnon
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Correspondence to Kenneth R. Johnson.

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Johnson, K.R., Longo-Guess, C.M. & Gagnon, L.H. A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice. Mamm Genome 26, 338–347 (2015). https://doi.org/10.1007/s00335-015-9574-y

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  • DOI: https://doi.org/10.1007/s00335-015-9574-y

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