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The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice.

The quantitative trait locus ahl8 is a key contributor to the early-onset, age-related hearing loss of DBA/2J mice. A nonsynonymous nucleotide substitution in the mouse fascin-2 gene (Fscn2) is responsible for this phenotype, confirmed by wild-type BAC transgene rescue of hearing loss in DBA/2J mice. In chickens and mice, FSCN2 protein is abundant in hair-cell stereocilia, the actin-rich structures comprising the mechanically sensitive hair bundle, and is concentrated toward stereocilia tips of the bundle's longest stereocilia. FSCN2 expression increases when these stereocilia differentially elongate, suggesting that FSCN2 controls filament growth, stiffens exposed stereocilia, or both. Because ahl8 accelerates hearing loss only in the presence of mutant cadherin 23, a component of hair-cell tip links, mechanotransduction and actin crosslinking must be functionally interrelated.

Pubmed ID: 20660251

Authors

  • Shin JB
  • Longo-Guess CM
  • Gagnon LH
  • Saylor KW
  • Dumont RA
  • Spinelli KJ
  • Pagana JM
  • Wilmarth PA
  • David LL
  • Gillespie PG
  • Johnson KR

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

July 21, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA34196
  • Agency: NIDCD NIH HHS, Id: DC005827
  • Agency: NIDCD NIH HHS, Id: K99 DC009412
  • Agency: NIDCD NIH HHS, Id: K99 DC009412
  • Agency: NIDCD NIH HHS, Id: P30 DC005983
  • Agency: NIDCD NIH HHS, Id: P30 DC005983
  • Agency: NIDCD NIH HHS, Id: P30 DC005983-09
  • Agency: NIDCD NIH HHS, Id: R00 DC009412
  • Agency: NIDCD NIH HHS, Id: R01 DC002368
  • Agency: NIDCD NIH HHS, Id: R01 DC002368
  • Agency: NIDCD NIH HHS, Id: R01 DC002368-17
  • Agency: NIDCD NIH HHS, Id: R01 DC005827
  • Agency: NIDCD NIH HHS, Id: R01 DC011034
  • Agency: NIDCD NIH HHS, Id: R21 DC008801
  • Agency: NIDCD NIH HHS, Id: R21 DC008801
  • Agency: NIDCD NIH HHS, Id: R21 DC008801-02

Mesh Terms

  • Actins
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Cadherins
  • Carrier Proteins
  • Chick Embryo
  • Disease Models, Animal
  • Disease Progression
  • Evoked Potentials, Auditory
  • Hair Cells, Auditory, Inner
  • Hearing Loss
  • Mice
  • Mice, Inbred DBA
  • Microfilament Proteins
  • Molecular Sequence Data
  • Mutation, Missense
  • Polymorphism, Genetic
  • Saccule and Utricle
  • Xenopus laevis