Hearing loss and cochlear abnormalities in the congenital hypothyroid (hyt/hyt) mouse

O’Malley, Bert W.; Li, Daqing; Turner, Donna S.

doi:10.1016/0378-5955(95)00111-g

Cited by 65 publications

(35 citation statements)

References 17 publications

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“…Changes in Purkinje cell morphology have been reported, which correlate with the effects of TH deficiency on Purkinje cells (Legrand 1979;Garcia-Atares et al 1998). The hr (hr rh allele) mutant mice are also deaf and show cochlear defects similar to congenital hypothyroid mutant (Tshr hyt ) mice (O'Malley et al 1995;Cachon-Gonzalez et al 1999). Inner ear defects also correlate with expression of TR␤ in the inner ear and deafness in TR␤ null mice (Bradley et al 1994;Forrest et al 1996).…”

Section: Hr Function In Vivomentioning

confidence: 99%

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

Potter¹,

Beaudoin²,

DeRenzo³

et al. 2001

Genes Dev.

167

179

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The mammalian hairless (hr) gene plays a critical role in the maintenance of hair growth. Although the hr gene has been identified, the biochemical function of its encoded protein (Hr) has remained obscure. Here, we show that Hr functions as a transcriptional corepressor for thyroid hormone receptors (TRs). We find that two independent regions of Hr mediate TR binding and that interaction requires a cluster of hydrophobic residues similar to the binding motifs proposed for nuclear receptor corepressors (N-CoR and SMRT). Similarly, we show that Hr binds to the same region of TR as known corepressors. We show that Hr interacts with histone deacetylases (HDACs) and is localized to matrix-associated deacetylase (MAD) bodies, indicating that the mechanism of Hr-mediated repression is likely through associated HDAC activity. Thus, Hr is a component of the corepressor machinery, and despite its lack of sequence identity with previously described corepressors, its mode of action is remarkably conserved. On the basis of its thyroid hormone-inducible and tissue-and developmental-specific expression, Hr likely defines a new class of nuclear receptor corepressors that serve a more specialized role than ubiquitous corepressors. The discovery that Hr is a corepressor provides a molecular basis for specific hair loss syndromes in both humans and mice.

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Section: Hr Function In Vivomentioning

confidence: 99%

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

Potter¹,

Beaudoin²,

DeRenzo³

et al. 2001

Genes Dev.

167

179

View full text Add to dashboard Cite

show abstract

“…Different animal models have been generated to study the role of thyroid hormones in the development of the auditory function. 22,[31][32][33][34][35][36][37] In most of these animal models, hearing loss is associated with various degree of disruption in the morphogenesis of different cochlear structures, including the tectorial membrane and the organ of Corti. In addition to its morphogenetic effect, thyroid hormones play also an important role in the myelination of the auditory nerve.…”

Section: Discussionmentioning

confidence: 99%

Mice Deficient for the Type II Transmembrane Serine Protease, TMPRSS1/hepsin, Exhibit Profound Hearing Loss

Guipponi

Tan

Cannon

et al. 2007

The American Journal of Pathology

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Defective proteolysis has been implicated in hearing loss through the discovery of mutations causing autosomal recessive nonsyndromic deafness in a type II transmembrane serine protease gene, TMPRSS3. To investigate their physiological function and the contribution of this family of proteases to the auditory function, we analyzed the hearing status of mice deficient for hepsin, also known as TMPRSS1. These mice exhibited profound hearing loss with elevated hearing thresholds compared with their heterozygous and wild-type littermates. Their cochleae showed abnormal tectorial membrane development, reduction in fiber compaction in the peripheral portion of the auditory nerve, and decreased expression of the myelin proteins myelin basic protein and myelin protein zero. In addition, reduced level of the large conductance voltage-and Ca 2؉-activated K ؉ channel was detected in the sensory hair cells of Tmprss1-null mice. We examined thyroid hormone levels in Tmprss1-deficient mice, as similar cochlear defects have been reported in animal models of hypothyroidism, and found significantly reduced free thyroxine levels. These data show that TMPRSS1 is required for normal auditory function. Hearing impairment present in Tmprss1-null mice is characterized by a combination of various structural, cellular, and molecular abnormalities that are likely to affect different cochlear processes. Hearing loss occurs in approximately 1 in 1000 children, and more than half of these cases can be considered to have a genetic origin. 1 The majority of the cases of hereditary deafness (70%) are nonsyndromic where impaired auditory function is the only clinical manifestation. In addition, hearing impairment affects 50% of individuals older than 80 years.2 Most of the cases of early-onset inherited hearing loss are due to single gene defects, and it has been proposed that genes responsible for monogenically inherited hearing loss may also be implicated in age-related hearing impairment (presbyacusis).3 Therefore, identifying the genes underlying hearing loss represents a major objective of current biomedical research. Most studies on the human ear can only be performed postmortem, making the investigation of early stages of pathogenicity impossible. Thus, understanding the molecular mechanisms of normal hearing and the pathogenic processes that lead to hearing loss relies extensively on animal models. The identification and study of the function of proteins encoded by deafness genes can be performed on mouse models.Recently, defective proteolysis has been implicated in the etiology of nonsyndromic hearing loss. Indeed, we and others have reported that deleterious mutations in the TMPRSS3 gene were responsible for nonsyndromic recessive hearing loss, 4 -9 suggesting that critical signaling pathways in the inner ear are controlled by proteolytic cleavage. TMPRSS3 is a member of the type II transmembrane serine proteases (TMPRSSs)

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“…Congenital thyroid disorders impair hearing, and iodine deficiency causes profound deafness (Dussault and Ruel, 1987;DeLong, 1993;Forrest, 1996). Furthermore, hypothyroidism causes deformities in the organ of Corti and has indicated a critical window of TH requirement during inner ear development preceding the onset of hearing (Deol, 1973;Uziel, 1986;O'Malley et al, 1995;Knipper et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Deficiency Affects Postnatal Spiking Activity and Expression of Ca²⁺and K⁺Channels in Rodent Inner Hair Cells

Brandt¹,

Kuhn²,

Münkner³

et al. 2007

J. Neurosci.

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Hearing loss and cochlear abnormalities in the congenital hypothyroid (hyt/hyt) mouse

Cited by 65 publications

References 17 publications

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

Mice Deficient for the Type II Transmembrane Serine Protease, TMPRSS1/hepsin, Exhibit Profound Hearing Loss

Thyroid Hormone Deficiency Affects Postnatal Spiking Activity and Expression of Ca²⁺and K⁺Channels in Rodent Inner Hair Cells

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Hearing loss and cochlear abnormalities in the congenital hypothyroid (hyt/hyt) mouse

Cited by 65 publications

References 17 publications

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor

Mice Deficient for the Type II Transmembrane Serine Protease, TMPRSS1/hepsin, Exhibit Profound Hearing Loss

Thyroid Hormone Deficiency Affects Postnatal Spiking Activity and Expression of Ca2+and K+Channels in Rodent Inner Hair Cells

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Thyroid Hormone Deficiency Affects Postnatal Spiking Activity and Expression of Ca²⁺and K⁺Channels in Rodent Inner Hair Cells