Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome

Everett, Lorraine A.; Belyantseva, Inna A.; Noben-Trauth, Konrad; Cantos, Raquel; Chen, Amy; Thakkar, Sneha I.; Hoogstraten-Miller, Shelley; Kachar, Bechara; Wu, Doris K.; Green, Eric D.

doi:10.1093/hmg/10.2.153

Cited by 393 publications

(346 citation statements)

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“…Several others have been described. The Slc26A4 (former PDS gene) knockout mouse develops ELH as early as embryonic day 15, and the mutant mouse is profoundly deaf (Everett et al, 2001). This mutation is associated with embryonic cochlear malformations not seen in most ELH conditions in patients, including MD, making this model less attractive for use in ELH modeling.…”

Section: Discussionmentioning

confidence: 99%

A mouse model with postnatal endolymphatic hydrops and hearing loss

et al. 2008

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Endolymphatic hydrops (ELH), hearing loss and neuronal degeneration occur together in a variety of clinically significant disorders, including Meniere's disease (MD). However, the sequence of these pathological changes and their relationship to each other are not well understood. In this regard, an animal model that spontaneously develops these features postnatally would be useful for research purposes. A search for such a model led us to the Phex Hyp-Duk mouse, a mutant allele of the Phex gene causing X-linked hypophosphatemic rickets. The hemizygous male (Phex Hyp-Duk /Y) was previously reported to exhibit various abnormalities during adulthood, including thickening of bone, ELH and hearing loss. The reported inner-ear phenotype was suggestive of progressive pathology and spontaneous development of ELH postnatally, but not conclusive. The main focuses of this report are to further characterize the inner ear phenotype in Phex Hyp-Duk /Y mice and to test the hypotheses that (a) the Phex Hyp-Duk /Y mouse develops ELH and hearing loss postnatally, and (b) the development of ELH in the Phex Hyp-Duk /Y mouse is associated with obstruction of the endolymphatic duct (ED) due to thickening of the surrounding bone. Auditory brainstem response (ABR) recordings at various times points and histological analysis of representative temporal bones reveal that Phex Hyp-Duk /Y mice typically develop adult onset, asymmetric, progressive hearing loss closely followed by the onset of ELH. ABR and histological data show that functional degeneration precedes structural degeneration. The major degenerative correlate of hearing loss and ELH in the mutants is the primary loss of spiral ganglion cells. Further, Phex Hyp-Duk /Y mice develop ELH without evidence of ED obstruction, supporting the idea that ELH can be induced by a mechanism other than the blockade of longitudinal flow of endolymphatic fluid, and occlusion of ED is not a prerequisite for the development of ELH in patients.

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Section: Discussionmentioning

confidence: 99%

A mouse model with postnatal endolymphatic hydrops and hearing loss

et al. 2008

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“…The expression of Pds is first activated in the endolymphatic sac and duct around 13 dpc. Pds knockout mice are deaf and show a variable spectrum of vestibular problems such as circling, head tilting, and bobbing behaviors (Everett et al 2001). Unlike other knockout mice that have defects in fluid homeostasis, Pds-/-mutants show swelling of the membranous labyrinth instead of shrinkage.…”

Section: Genes That Affect Fluid Homeostasismentioning

confidence: 99%

“…The swelling later spreads into the vestibular and cochlear regions. The deafness and balancing problems in these mice are most likely due to sensory hair-cell degeneration resulting from an ionic imbalance within the endolymph (Everett et al 2001). Functional studies in frog (Xenopus) oocytes suggest that PENDRIN is a chloride and iodide transporter (Scott et al 1999).…”

Section: Genes That Affect Fluid Homeostasismentioning

confidence: 99%

Molecular Genetics of Vestibular Organ Development

Chang¹,

Cole²,

Cantos³

et al. 2004

The Vestibular System

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“…Pendrin specifically transports chloride and iodide and is thought to be important for endolymphatic fluid resorption in the inner ear (Everett et al, 1999). Pds −/− mice lack otoconia or develop giant otoconia (Everett et al, 2001), but also have significant defects in the remainder of the ear, including stereociliary degeneration. Foxi1, a forkhead transcription factor, regulates expression of Pendrin in the developing inner ear.…”

Section: Establish the Ionic Environmentmentioning

confidence: 99%

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

Hughes

Thalmann

et al. 2006

Brain Research

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Human vestibular dysfunction is an increasing clinical problem. Degeneration or displacement of otoconia is a significant etiology of age-related balance disorders and Benign Positional Vertigo (BPV). In addition, commonly used antibiotics, such as aminoglycoside antibiotics, can lead to disruption of otoconial structure and function. Despite such clinical significance, relatively little information has been compiled about the development and maintenance of otoconia in humans. Recent studies in model organisms and other mammalian organ systems have revealed some of the proteins and processes required for the normal biomineralization of otoconia and otoliths in the inner ear of vertebrates. Orchestration of extracellular biomineralization requires bringing together ionic and proteinaceous components in time and space. Coordination of these events requires the normal formation of the otocyst and sensory maculae, specific secretion and localization of extracellular matrix proteins, as well as tight regulation of the endolymph ionic environment. Disruption of any of these processes can lead to the formation of abnormally shaped, or ectopic, otoconia, or otoconial agenesis. We propose that normal generation of otoconia requires a complex temporal and spatial control of developmental and biochemical events. In this review, we suggest a new hypothetical model for normal otoconial and otolith formation based on matrix vesicle mineralization in bone which we believe to be supported by information from existing mutants, morphants, and biochemical studies.

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Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome

Cited by 393 publications

References 50 publications

A mouse model with postnatal endolymphatic hydrops and hearing loss

A mouse model with postnatal endolymphatic hydrops and hearing loss

Molecular Genetics of Vestibular Organ Development

Mixing model systems: Using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development

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