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.
Shin
Jung-Bum
JB
Oregon Hearing Research Center, Oregon Health & Science University, Portland, Oregon 97239, USA.
Longo-Guess
Chantal M
CM
Gagnon
Leona H
LH
Saylor
Katherine W
KW
Dumont
Rachel A
RA
Spinelli
Kateri J
KJ
Pagana
James M
JM
Wilmarth
Phillip A
PA
David
Larry L
LL
Gillespie
Peter G
PG
Johnson
Kenneth R
KR
D000199:Actins / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D002642:Chick Embryo; D004195:Disease Models, Animal; D018450:Disease Progression; D005072:Evoked Potentials, Auditory; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D034381:Hearing Loss / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D012444:Saccule and Utricle / Q000648:ultrastructure; D014982:Xenopus laevis
D000199:Actins; D015820:Cadherins; D002352:Carrier Proteins; C499091:Cdh23 protein, mouse; D008840:Microfilament Proteins; C020324:fascin