Academic journal article Genetics

Multiple Quantitative Trait Loci Modify Cochlear Hair Cell Degeneration in the Beethoven (Tmc1^sub Bth^) Mouse Model of Progressive Hearing Loss DFNA36

Academic journal article Genetics

Multiple Quantitative Trait Loci Modify Cochlear Hair Cell Degeneration in the Beethoven (Tmc1^sub Bth^) Mouse Model of Progressive Hearing Loss DFNA36

Article excerpt

ABSTRACT

Dominant mutations of transmembrane channel-like gene 1 (TMC1) cause progressive sensorineural hearing loss in humans and Beethoven (Tmc1^sup Bth/+^) mice. Here we show that Tmc1^sup Bth/+^ mice on a C3HeB/FeJ strain background have selective degeneration of inner hair cells while outer hair cells remain structurally and functionally intact. Inner hair cells primarily function as afferent sensory cells, whereas outer hair cells are electromotile amplifiers of auditory stimuli that can be functionally assessed by distortion product otoacoustic emission (DPOAE) analysis. When C3H-Tmc1^sup Bth/Bth^ is crossed with either C57BL/6J or DBA/2J wild-type mice, F^sub 1^ hybrid Tmc1^sup Bth/+^ progeny have increased hearing loss associated with increased degeneration of outer hair cells and diminution of DPOAE amplitudes but no difference in degeneration of inner hair cells. We mapped at least one quantitative trait locus (QTL), Tmc1m1, for DPOAE amplitude on chromosome 2 in [(C/B)F^sub 1^ × C]N^sub 2^-Tmc1^sup Bth/+^ backcross progeny, and three other QTL on chromosomes 11 (Tmc1m2), 12 (Tmc1m3), and 5 (Tmc1m4) in [(C/D)F^sub 1^ × C]N^sub 2^-Tmc1^sup Bth/+^ progeny. The polygenic basis of outer hair cell degeneration in Beethoven mice provides a model system for the dissection of common, complex hearing loss phenotypes, such as presbycusis, that involve outer hair cell degeneration in humans.

THERE are >100 loci at which mutations cause monogenic nonsyndromic sensorineural hearing loss (SNHL) in humans (FRIEDMAN and GRIFFITH 2003). Most autosomal recessive loci are associated with prelingual severe to profound SNHL, whereas autosomal dominant alleles typically cause postlingual progressive SNHL (GRIFFITH and FRIEDMAN 2002). The specific causes of SNHL associated with advanced age (presbycusis) are unknown, but thought to comprise a complex combination of genetic and environmental factors (SCHULTZ et al. 2005). Mutant mice are important tools for identifying these factors, their function in the auditory system, and the pathogenesis of hearing loss (HAIDER et al. 2002). For example, studies of polygenic age-related hearing loss in inbred mouse strains (NOBEN-TRAUTH et al. 2003) facilitated the recent identification of a geneticmodifier of hearing loss in humans (SCHULTZ et al. 2005), demonstrating the applicability of mouse models to the dissection of complex hearing loss traits in humans.

Dominant and recessive mutations of transmembrane channel-like gene 1 (TMC1) cause nonsyndromic SNHL at the DFNA36 and DFNB7/B11 loci, respectively (KURIMA et al. 2002, 2003). TMC1 encodes a polytopic transmembrane protein of unknown function that is expressed in cochlear hair cells (KURIMA et al. 2002; VREUGDE et al. 2002). In mice, dominant and recessive mutations of Tmc1 cause SNHL in the Beethoven (Bth) and deafness (dn) mouse lines, respectively (KURIMA et al. 2002; VREUGDE et al. 2002). Whereas DFNB7/B11 and dn homozygotes have severe to profound congenital hearing loss, heterozygous carriers of Bth and DFNA36 mutations have delayed-onset, progressive SNHL. SNHL in Beethoven and deafness mice is associated with rapid degeneration of cochlear hair cells (BOCK and STEEL 1983; VREUGDE et al. 2002), indicating that Tmc1 is required for normal hair cell function or survival.

The mammalian cochlea contains two types of hair cells distinguished by their location, morphology, and function (FROLENKOV et al. 2004). In general terms, inner hair cells (IHCs) have primarily afferent innervation and function as sensory cells transducing and transmitting auditory signals to the central nervous system. Outer hair cells (OHCs) receive principally efferent innervation and have a distinctive electromotile property postulated to underlie active biomechanical amplification of auditory stimuli. As a result of this active amplification, OHCs generate sounds known as otoacoustic emissions (OAEs) that can be measured noninvasively in living humans andmice with a sensitive microphone in the external auditory canal. …

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