Characterization of a New Mouse Mutant, Flouncer, with a Balance Defect and Inner Ear Malformation

Pau, Henry; Hawker, Kelvin; Fuchs, Helmut; Angelis, Martin Hrabé de; Steel, Karen P.

doi:10.1097/00129492-200409000-00010

Cited by 25 publications

(20 citation statements)

References 27 publications

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“…Three rows of OHCs were observed in most cochlear regions, and both wild type and Chd7 Gt/+ mice had short stretches (5-6 cells) of four rows of OHCs irregularly spaced predominantly in the apex, but these areas were more abundant in Chd7 Gt/+ , consistent with our ABR data (Fig. 2) and with previous reports showing that intermittent supernumerary rows of hair cells may contribute to sensorineural HL in Chd7 haploinsufficient mice (Pau et al, 2004). …”

Section: Resultssupporting

confidence: 92%

Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome

et al. 2011

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Heterozygous mutations in the gene encoding chromodomain-DNA-binding-protein 7 (CHD7) cause CHARGE syndrome, a multiple anomaly condition which includes vestibular dysfunction and hearing loss. Mice with heterozygous Chd7 mutations exhibit semicircular canal dysgenesis and abnormal inner ear neurogenesis, and are an excellent model of CHARGE syndrome. Here we characterized Chd7 expression in mature middle and inner ears, analyzed morphological features of mutant ears and tested whether Chd7 mutant mice have altered responses to noise exposure and correlated those responses to inner and middle ear structure. We found that Chd7 is highly expressed in mature inner and outer hair cells, spiral ganglion neurons, vestibular sensory epithelia and middle ear ossicles. There were no obvious defects in individual hair cell morphology by Prestin immunostaining or scanning electron microscopy, and cochlear innervation appeared normal in Chd7Gt/+ mice. Hearing thresholds by auditory brainstem response (ABR) testing were elevated at 4 and 16 kHz in Chd7Gt/+ mice, and there were reduced distortion product otoacoustic emissions (DPOAE). Exposure of Chd7Gt/+ mice to broadband noise resulted in variable degrees of hair cell loss which inversely correlated with severity of stapedial defects. The degrees of hair cell loss and threshold shifts after noise exposure were more severe in wild type mice than in mutants. Together, these data indicate that Chd7Gt/+ mice have combined conductive and sensorineural hearing loss, correlating with changes in both middle and inner ears.

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Section: Resultssupporting

confidence: 92%

Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome

et al. 2011

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“…Looper displayed severe hypoplasia of the lateral semicircular canal and variable hypoplasia of the other canals. This is consistent with malformation of the lateral semicircular canal in other Chd7 mouse mutants [11], [28] and in CHARGE patients, where the lateral canal is always affected and other canals are occasionally mildly affected [30].…”

Section: Discussionsupporting

confidence: 87%

“…Cochlear histology was normal but ossicles were abnormal and the stapes fixed. Malformations of the ossicle chain were similar to those reported for other Chd7 mutants [28]. µCT images of these ossicle abnormalities have not been published before.…”

Section: Discussionsupporting

confidence: 82%

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CHD7 Deficiency in “Looper”, a New Mouse Model of CHARGE Syndrome, Results in Ossicle Malformation, Otosclerosis and Hearing Impairment

et al. 2014

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CHARGE syndrome is a rare human disorder caused by mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7). Characteristics of CHARGE are varied and include developmental ear and hearing anomalies. Here we report a novel mouse model of CHD7 dysfunction, termed Looper. The Looper strain harbours a nonsense mutation (c.5690C>A, p.S1897X) within the Chd7 gene. Looper mice exhibit many of the clinical features of the human syndrome, consistent with previously reported CHARGE models, including growth retardation, facial asymmetry, vestibular defects, eye anomalies, hyperactivity, ossicle malformation, hearing loss and vestibular dysfunction. Looper mice display an otosclerosis-like fusion of the stapes footplate to the cochlear oval window and blepharoconjunctivitis but not coloboma. Looper mice are hyperactive and have vestibular dysfunction but do not display motor impairment.

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“…Most of these alleles had been generated using Ethyl-Nitrosourea (ENU) in a screen for mutations that result in hyperactivity and circling behaviors [Alavizadeh et al, 2001; Hawker et al, 2005; Kiernan et al, 2002; Nolan et al, 1995; Pau et al, 2004; Pickard et al, 1995]. Each of these mutant mice harbors a heterozygous loss of function variant in the Chd7 gene, and exhibits phenotypes including hyperactivity, head-bobbing, circling, and structural abnormalities of the semicircular canals.…”

Section: Chd7 Mutant Mouse Models and Phenotypesmentioning

confidence: 99%

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures

Choo

Tawfik

Martin

et al. 2017

American J of Med Genetics Pt C

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The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.

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Characterization of a New Mouse Mutant, Flouncer, with a Balance Defect and Inner Ear Malformation

Abstract: The lateral semicircular canal has been described to be the most commonly affected part of the inner ear in humans, and flouncer provides a mouse model for genetic and developmental analysis of such defects.

Cited by 25 publications

References 27 publications

Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome

Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome

CHD7 Deficiency in “Looper”, a New Mouse Model of CHARGE Syndrome, Results in Ossicle Malformation, Otosclerosis and Hearing Impairment

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures

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