Deafness and Permanently Reduced Potassium Channel Gene Expression and Function in HypothyroidPit1^dwMutants

Abstract

The absence of thyroid hormone (TH) during late gestation and early infancy can cause irreparable deafness in both humans and rodents. A variety of rodent models have been utilized in an effort to identify the underlying molecular mechanism. Here, we characterize a mouse model of secondary hypothyroidism, pituitary transcription factor 1 (Pit1dw), which has profound, congenital deafness that is rescued by oral TH replacement. These mutants have tectorial membrane abnormalities, including a prominent Hensen's stripe, elevated β-tectorin composition, and disrupted striated-sheet matrix. They lack distortion product otoacoustic emissions and cochlear microphonic responses, and exhibit reduced endocochlear potentials, suggesting defects in outer hair cell function and potassium recycling. Auditory system and hair cell physiology, histology and anatomy studies reveal novel defects of hormone deficiency related to deafness: (1) permanently impaired expression of KCNJ10 in the stria vascularis of Pit1dw mice, which likely contributes to the reduced endocochlear potential, (2) significant outer hair cell loss in the mutants, which may result from cellular stress induced by the lower KCNQ4 expression and current levels in Pit1dw mutant outer hair cells and (3) sensory and strial cell deterioration, which may have implications for thyroid hormone dysregulation in age related hearing impairment. In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1dw mice.

A Modifier Gene Alleviates Hypothyroidism-Induced Hearing Impairment in Pou1f1dw Dwarf Mice

“…Another hearing-related QTL on Chr 2, which could be equivalent to Mtap1a or Mdwh, modifies the degree of hearing loss in Beethoven mutant mice, which carry a mutation in Tmc1 (Noguchi et al 2006). Intriguingly, the phenotype of these mice is outer hair cell loss and reduced DPOAE, the same as that observed in Pou1f1 dw mutants (Mustapha et al 2009). …”

“…Third, MTAP1A interacts directly with the calcium-activated potassium channel BKCa (Park et al 2004), and defects in Kcnma1, which encodes one of the BKCa subunits, cause progressive hearing loss and absence of KCNQ4 expression (Ruttiger et al 2004). Fourth, KCNQ4 is regulated by the thyroid hormone receptors TRa1 and TRb in outer hair cells (Winter et al 2006), and its expression is reduced in Pou1f1 dw mutant outer hair cells (Mustapha et al 2009). Finally, recent studies demonstrate that TH is essential for morphological and functional maturation of inner hair cell (IHC) ribbon synapses (Brandt et al 2007;Sendin et al 2007).…”

“…Given the pleiotropic effects that the thyroid hormone has on cochlear development (Mustapha et al 2009), Mdwh could consist of multiple genes, possibly including Mtap1a, whose combined actions protect against hypothyroidisminduced hearing impairment in Pou1f1 dw mutants. The information gleaned by genotyping the DW/J-Pou1f1 dw genome Figure 6 The Mtap1a allele correlates with, but is neither necessary nor sufficient for, protection of hearing in Pou1f1 dw mice.…”

“…We chose the Pou1f1 dw mutant mice because of the severity of their hearing impairment, their responsiveness to TH replacement, and their wellcharacterized cochlear pathologies (Mustapha et al 2009). Detailed morphological, physiological, and gene expression analyses of Pou1f1 dw mutants during the course of cochlear development revealed tectorial membrane abnormalities, loss of outer hair cells (OHCs) preceded by their compromised function [as evidenced by an absence of distortion product otoacoustic emissions (DPOAE) and cochlear microphonics], reduced endocochlear potential, and reduced expression of potassium channel proteins (KCNJ10 in the stria vascularis and KCNQ4 in OHCs), all of which are likely contributors to the severe hearing impairment of these mutant mice (Mustapha et al 2009). Similar features, including lack of DPOAE, reduced endocochlear potential, and tectorial membrane abnormalities, are characteristic of the Cga knockout mice (Karolyi et al 2007).…”

Hearing levels in patients with subclinical hypothyroidism

“…Yapılan çalışmalar daha çok hayvan deneylerine dayanmaktadır. [3] İnsanlarda hipotiroidinin işitme üzerindeki etkisi temel olarak saf ses odyometri ile değerlendirilmektedir.…”