Mutations of MYO6 Are Associated with Recessive Deafness, DFNB37

Ahmed, Zubair M.; Morell, Robert J.; Riazuddin, Saima; Gropman, Andrea; Shaukat, Shahzad; Ahmad, Mussaber M.; Mohiddin, Saidi A.; Fananapazir, Lameh; Caruso, Rafael C.; Husnain, Tayyab; Khan, Shaheen N.; Riazuddin, Sheikh; Griffith, Andrew J.; Friedman, Thomas B.; Wilcox, Edward R.

doi:10.1086/375122

Cited by 177 publications

(173 citation statements)

References 29 publications

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“…All three intervals contain genes that have been linked to deafness and hair cell function. These are the Mass1 gene (rueda mice; Usher Syndrome Type 2C) (Weston et al, 2004), the Myo6 gene (twist mice; DFNA22, DFNB37) (Melchionda et al, 2001;Ahmed et al, 2003), and the otoferlin gene ( pachanga mice, DFNB9) (Migliosi et al, 2002;RodriguezBallesteros et al, 2003;Varga et al, 2003Varga et al, , 2006Tekin et al, 2005;Wang et al, 2005). In rueda mice, we identified a G-to-T transversion in the Mass1 gene, which is uniquely homozygous in mice with an auditory phenotype (Fig.…”

Section: Positional Cloningmentioning

confidence: 79%

A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function

Schwander¹,

Sczaniecka²,

Grillet³

et al. 2007

J. Neurosci.

162

185

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Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to the pejvakin gene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the human pejvakin gene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, the pejvakin allele described here introduces a premature stop codon, causes outer hair cell defects, and leads to progressive hearing loss. We also identified a novel allele of the human pejvakin gene in an Iranian pedigree that is afflicted with progressive hearing loss. Our findings suggest that the mechanisms of pathogenesis associated with pejvakin mutations are more diverse than previously appreciated. More generally, our findings demonstrate that recessive screens in mice are powerful tools for identifying genes that control the development and function of mechanosensory hair cells and cause deafness in humans, as well as generating animal models for disease.

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Section: Positional Cloningmentioning

confidence: 79%

A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function

Schwander¹,

Sczaniecka²,

Grillet³

et al. 2007

J. Neurosci.

162

185

View full text Add to dashboard Cite

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“…Myosin VI mutations in mice, fish, and humans result in deafness due to degeneration of hair cell stereocilia (Avraham et al 1995;Self et al 1999;Ahmed et al 2003;Kappler et al 2004). In addition, vertebrate myosin VI has been implicated in processes similar to those affected in Drosophila, such as endocytosis, cell adhesion, and basolateral sorting (Dance et al 2004;Ameen and Apodaca 2007;Au et al 2007;Maddugoda et al 2007;Morriswood et al 2007).…”

Section: R235mentioning

confidence: 99%

Genetic Characterization of the Drosophila jaguar322 Mutant Reveals That Complete Myosin VI Loss of Function Is Not Lethal

Morrison

Miller

2008

Genetics

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Myosin VI is an actin-based motor that has been implicated in many cellular processes. Studies in vertebrates have demonstrated that animals lacking this ubiquitously expressed myosin are viable. However in Drosophila, myosin VI loss of function has been thought to be lethal. We show here that complete loss of myosin VI is not lethal in flies and that the previously reported lethality of the null mutation ( jar 322 ) is most likely due to deletion of a neighboring gene. Maternally provided myosin VI does not account for the survival of myosin VI null animals. Mutant animals are recovered at a lower than expected Mendelian frequency, suggesting that myosin VI participates in processes which contribute to normal development, but its participation is not essential.

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“…This C442Y mutation in the motor domain is close to the ATP binding pocket and dramatically increases the rate of ADP dissociation (29). Several different mutations in the myosin VI gene have also been identified in three Pakistani families suffering from recessive deafness (30).…”

mentioning

confidence: 99%

Loss of Myosin VI No Insert Isoform (NoI) Induces a Defect in Clathrin-mediated Endocytosis and Leads to Caveolar Endocytosis of Transferrin Receptor

Puri

2009

Journal of Biological Chemistry

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Myosin VI is a motor protein that moves toward the minus end of actin filaments. It is involved in clathrin-mediated endocytosis and associates with clathrin-coated pits/vesicles at the plasma membrane. In this article the effect of the loss of myosin VI no insert isoform (NoI) on endocytosis in nonpolarized cells was examined. The absence of myosin VI in fibroblasts derived from the Snell's waltzer mouse (myosin VI knock-out) gives rise to defective clathrin-mediated endocytosis with shallow clathrin-coated pits and a strong reduction in the internalization of clathrin-coated vesicles. To compensate for this defect in clathrin-mediated endocytosis, plasma membrane receptors such as the transferrin receptor (TfR) are internalized by a caveola-dependent pathway. Moreover the clathrin adaptor protein, AP-2, necessary for TfR internalization, follows the receptor and relocalizes in caveolae in Snell's waltzer fibroblasts.In eukaryotic cells diverse endocytic uptake pathways occur at the plasma membrane; these have crucial roles in signal transduction, immune surveillance, antigen presentation, cellcell communication, and cellular homeostasis. Clathrin-mediated endocytosis is by far the best characterized pathway by which cells internalize protein and lipid molecules, although at least three other basic mechanisms, caveola-mediated endocytosis, macropinocytosis, and clathrin-and caveola-independent endocytosis, are also known to operate (1, 2). Recent results have suggested that signaling receptors such as epidermal growth factor receptor (EGFR) 2 and other receptor tyrosine kinases could be endocytosed not only by the clathrin-dependent pathway but also by alternative pathways involving circular dorsal ruffles (3) or by caveolin/raft-dependent endocytosis (4 -7). Moreover, it was recently observed that the transferrin receptor (TfR), a nonsignaling receptor that is internalized canonically by clathrin-mediated endocytosis, can also be endocytosed by a clathrin/dynamin-independent, cholesterol-dependent pathway (8).Caveolae were first observed more than 50 years ago on the surface of endothelial cells; caveola-mediated endocytosis is the best described clathrin-independent uptake route. Caveolae, flask-shaped invaginations of the plasma membrane, are specialized lipid raft domains that are rich in cholesterol and sphingolipids, with shape and structural organization maintained by the integral membrane protein caveolin. Although not all mammalian cells express caveolin, caveolae are very abundant at the plasma membrane of fibroblasts, adipocytes, and endothelial and smooth muscle cells; however, the precise uptake mechanism involved and how it is triggered and regulated are thus far rather poorly understood.Motor proteins such as myosin VI have been shown to be involved in clathrin-mediated endocytosis (9 -13). Myosin VI is a unique actin-based motor protein that moves toward the minus end of actin filaments, in the opposite direction to all other myosins characterized thus far (14). In mammalian cells, four alternat...

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Mutations of MYO6 Are Associated with Recessive Deafness, DFNB37

Cited by 177 publications

References 29 publications

A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function

A Forward Genetics Screen in Mice Identifies Recessive Deafness Traits and Reveals That Pejvakin Is Essential for Outer Hair Cell Function

Genetic Characterization of the Drosophila jaguar322 Mutant Reveals That Complete Myosin VI Loss of Function Is Not Lethal

Loss of Myosin VI No Insert Isoform (NoI) Induces a Defect in Clathrin-mediated Endocytosis and Leads to Caveolar Endocytosis of Transferrin Receptor

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