Strain background effects and genetic modifiers of hearing in mice

Johnson, Kenneth R.; Zheng, Qing Yin; Noben-Trauth, Konrad

doi:10.1016/j.brainres.2006.02.021

Cited by 119 publications

(87 citation statements)

References 73 publications

(73 reference statements)

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“…Similar to the PDZD7 mutation we discovered in FCa, an additional heterozygous MYO7A (USH1B) truncation produced a dramatically enhanced phenotype (19). Epistatic interaction was also reported in mice with a hypomorphic Cdh23 (USH1D) allele that modified hearing impairment due to a homozygous Gpr98 mutation (20). In Bardet-Biedl syndrome (BBS), another genetically heterogeneous recessive RP disorder, heterozygous mutations in BBS1, BBS2, or BBS6 correlate with a more severe phenotype in patients with biallelic mutations at a second BBS locus (21,22).…”

Section: Discussionsupporting

confidence: 66%

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Ebermann¹,

Phillips²,

Liebau³

et al. 2010

J. Clin. Invest.

198

167

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Usher syndrome is a genetically heterogeneous recessive disease characterized by hearing loss and retinitis pigmentosa (RP). It frequently presents with unexplained, often intrafamilial, variability of the visual phenotype. Although 9 genes have been linked with Usher syndrome, many patients do not have mutations in any of these genes, suggesting that there are still unidentified genes involved in the syndrome. Here, we have determined that mutations in PDZ domain-containing 7 (PDZD7), which encodes a homolog of proteins mutated in Usher syndrome subtype 1C (USH1C) and USH2D, contribute to Usher syndrome. Mutations in PDZD7 were identified only in patients with mutations in other known Usher genes. In a set of sisters, each with a homozygous mutation in USH2A, a frame-shift mutation in PDZD7 was present in the sister with more severe RP and earlier disease onset. Further, heterozygous PDZD7 mutations were present in patients with truncating mutations in USH2A, G protein-coupled receptor 98 (GPR98; also known as USH2C), and an unidentified locus. We validated the human genotypes using zebrafish, and our findings were consistent with digenic inheritance of PDZD7 and GPR98, and with PDZD7 as a retinal disease modifier in patients with USH2A. Pdzd7 knockdown produced an Usher-like phenotype in zebrafish, exacerbated retinal cell death in combination with ush2a or gpr98, and reduced Gpr98 localization in the region of the photoreceptor connecting cilium. Our data challenge the view of Usher syndrome as a traditional Mendelian disorder and support the reclassification of Usher syndrome as an oligogenic disease.

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Section: Discussionsupporting

confidence: 66%

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Ebermann¹,

Phillips²,

Liebau³

et al. 2010

J. Clin. Invest.

198

167

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“…To date, mapping of hearing-related genes in mice has relied entirely on distributions of hearing thresholds e.g., (Johnson et al, 2006). Here we report a surprisingly robust phenotype revealed only by noise exposure that is manifested through the EP rather than threshold, and is closely tied to a set of well delineated pathologies of cochlear lateral wall and spiral limbus.…”

Section: Discussionmentioning

confidence: 78%

Genetic dependence of cochlear cells and structures injured by noise

Ohlemiller¹,

Gagnon²

2007

Hearing Research

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The acute and permanent effects of a single damaging noise exposure were compared in CBA/J, C57BL/6 (B6), and closely related strains of mice. Two hrs of broadband noise (4-45 kHz) at 110 dB SPL led to temporary reduction in the endocochlear potential (EP) of CBA/J and CBA/CaJ (CBA) mice and acute cellular changes in cochlear stria vascularis and spiral ligament. For the same exposure, B6 mice showed no EP reduction and little of the pathology seen in CBA. Eight weeks after exposure, all mice showed a normal EP, but only CBA mice showed injury and cell loss in cochlear lateral wall, despite the fact that B6 sustained larger permanent threshold shifts. Examination of noise injury in B6 congenics carrying alternate alleles of genes encoding otocadherin (Cdh23), agouti protein, and tyrosinase (albinism) indicated that none of these loci can account for the strain differences observed. Examination of B6xCBA F1 mice and F1xB6 N2 mice further indicated that susceptibility to noise-related EP reduction and associated cell pathology are inherited in an autosomal dominant manner, and are established by one or a few large effect quantitative trait loci. Findings support a common genetic basis for an entire constellation of noise related cochlear pathologies in cochlear lateral wall and spiral limbus. Even within species, cellular targets of acute and permanent cochlear noise injury may vary with genetic makeup.

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“…Phenotypically, mice that are hetereozygous for the jerker mutation (jerker heterozygotes) appear relatively normal. Although aged jerker heterozygotes have been reported to show stereociliary and hair cell degeneration [32,33], it is presently unclear whether these defects are related to the jerker mutation or are associated with age-related hearing loss, which is evident in a number of inbred mouse strains [36]. Unfortunately, the reports of cochlear defects in aged jerker heterozygotes [32,33] used mice of a different background strain (CBA) as wild-type controls, and to our knowledge wild-type mice of the standard inbred jerker mouse strain (JE/LeJ, stock number 000249) obtained from the Jackson Laboratory (Bar Harbor, Maine, USA) have not yet been tested for age-related hearing loss.…”

Section: Jerker Deafness Mutation In the Mouse Espin Genementioning

confidence: 99%

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

Sekerková

Zheng

Loomis

et al. 2006

Cell. Mol. Life Sci.

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The espins are novel actin-bundling proteins that are produced in multiple isoforms from a single gene. They are present at high concentration in the parallel actin bundle of hair cell stereocilia and are the target of deafness mutations in mice and humans. Espins are also enriched in the microvilli of taste receptor cells, solitary chemoreceptor cells, vomeronasal sensory neurons and Merkel cells, suggesting that espins play important roles in the microvillar projections of vertebrate sensory cells. Espins are potent actin-bundling proteins that are not inhibited by Ca 2+ . In cells, they efficiently elongate parallel actin bundles and, thereby, help determine the steady-state length of microvilli and stereocilia. Espins bind actin monomer via their WH2 domain and can assemble actin bundles in cells. Certain espin isoforms can also bind phosphatidylinositol 4,5-bisphosphate, profilins or SH3 proteins. These biological activities distinguish espins from other actin-bundling proteins and may make them well-suited to sensory cells. KeywordsEspin; actin; hair cell; stereocilia; microvilli; sensory; deafness; taste The stereocilia and microvilli of vertebrate sensory cells and their actinbundling proteinsMany classes of vertebrate sensory cells detect chemical or mechanical stimuli through microvilli or their derivatives, such as stereocilia. These relatively long-lived, fingerlike specializations of the plasma membrane are built around a common cytoskeletal element -the parallel actin bundle (PAB) [1]. PABs consist of tightly packed collections of actin filaments cross-linked by actin-bundling proteins. The filaments are aligned along their longitudinal axis and display a uniform polarity with respect to their preferred ends for actin monomer addition, which in microvilli and stereocilia is positioned at the distal tip. The PAB displays hallmarks of a supramolecular scaffold that determines the placement, dimensions, flexibility and signaling properties of microvilli and stereocilia. Although filopodia also contain a PAB at their core and are believed to sense the local environment, they are considerably more dynamic and differ significantly from microvilli and stereocilia in their molecular composition and biogenesis [2].

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Strain background effects and genetic modifiers of hearing in mice

Cited by 119 publications

References 73 publications

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

PDZD7 is a modifier of retinal disease and a contributor to digenic Usher syndrome

Genetic dependence of cochlear cells and structures injured by noise

Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli

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