Gipc3 mutations associated with audiogenic seizures and sensorineural hearing loss in mouse and human

Abstract

Sensorineural hearing loss affects the quality of life and communication of millions of people, but the underlying molecular mechanisms remain elusive. Here, we identify mutations in Gipc3 underlying progressive sensorineural hearing loss (age-related hearing loss 5, ahl5) and audiogenic seizures (juvenile audiogenic monogenic seizure 1, jams1) in mice and autosomal recessive deafness DFNB15 and DFNB95 in humans. Gipc3 localizes to inner ear sensory hair cells and spiral ganglion. A missense mutation in the PDZ domain has an attenuating effect on mechanotransduction and the acquisition of mature inner hair cell potassium currents. Magnitude and temporal progression of wave I amplitude of afferent neurons correlate with susceptibility and resistance to audiogenic seizures. The Gipc3343A allele disrupts the structure of the stereocilia bundle and affects long-term function of auditory hair cells and spiral ganglion neurons. Our study suggests a pivotal role of Gipc3 in acoustic signal acquisition and propagation in cochlear hair cells.

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

“…However, ABR amplitudes to suprathreshold click stimuli were altered in ephrin-A5 À / À animals. In particular, ABR peak 1 amplitude reflecting the summed activity of cochlear afferents 33,34 is significantly decreased at several intensity levels and, on average, is 40% smaller in mice lacking ephrin-A5 (Fig. 6b,c).…”

Gipc1 has a dual role in Vangl2 trafficking and hair bundle integrity in the inner ear

“…In the course of this study, GIPC3, another member of the GIPC family was associated with progressive hearing loss in humans and mice (Charizopoulou et al, 2011). Interestingly, in the mutant mice, the identified mutation affected the PDZ domain of Gipc3, leading to early postnatal disruption of hair bundle structural integrity.…”

Genetics of Nonsyndromic Recessively Inherited Moderate to Severe and Progressive Deafness in Humans

“…Intra-or inter-familal phenotypic variability is also observed due to progression of hearing loss (DFNB7,DFNB8,DFNB25,DFNB30,DFNB59,DFNB72/95,DFNB77,DFNB79,DFNB84 and DFNB91) (Charizopoulou et al, 2011;de Heer et al, 2011;Ebermann et al, 2007b;Grillet et al, 2009;Li et al, 2010;Rehman et al, 2011;Schraders et al, 2010a;Schraders et al, 2010b;Sirmaci et al, 2010;Walsh et al, 2002;Weegerink et al, 2011). Younger individuals with mutations in BSND (DFNB73) also have a less severe degree of hearing loss which suggests a progressive nature of their hearing loss .…”

“…A mutation affecting PDZ domain of GIPC3 has also been reported in mice which causes progressive hearing loss, ahl5 (Charizopoulou et al, 2011). The mice have a moderate hearing loss at one month of age which progresses to profound in degree by 1 year of age.…”

“…The hearing loss in second individual was 80 dB HL at 3 months which seemed to be stable as it only progressed to 90 dB HL by age of 14 years. (Charizopoulou et al, 2011). The mutation in GIPC3 identified in the Dutch family introduces a stop codon in exon 6 (p.W301X) truncating the C-terminal.…”