Nonsyndromic Deafness DFNA1 Associated with Mutation of a Human Homolog of the
            <i>Drosophila</i>
            Gene
            <i>diaphanous</i>

Lynch, Eric D.; Lee, Ming K.; Morrow, Jan E.; Welcsh, Piri; León, Pedro; King, Mary Claire

doi:10.1126/science.278.5341.1315

Cited by 402 publications

(271 citation statements)

References 31 publications

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“…1, E and F), in keeping with the published findings of others who have reported PKD2 on kidney epithelial cell cilia (8,9). We theorized that cilia might be a possible site for interaction between PKD2 and mDia1, since cilia are microtubule-based structures and mDia1 and mDia2 have both been reported to interact with microtubules (31,32). None of our efforts to demonstrate the presence of mDia1 on cilia by confocal microscopy were successful.…”

Section: Mdia1-dependent Localization Of Pkd2 To Mitotic Spindlessupporting

confidence: 68%

“…The diaphanous subfamily appears to primarily function in cytokinesis and in cytoskeletal rearrangement and stabilization. Consistent with its role in actin polymerization in hair cells of the ear, naturally occurring mutations in mDia1 cause nonsyndromic deafness in humans (32). mDia1 was also recently found to be essential for mechanotransduction in response to integrin activation in SV-80 human fibroblast cells (33) but is not involved in the regulation of integrin-mediated cell adhesion in Jurkat cells (34).…”

mentioning

confidence: 87%

“…mDia1, because a naturally occurring mutation truncating these residues results in deafness (32). We have analyzed cell lysates transfected with either GFP-⌬N3mDia1 (Fig.…”

Section: Mdia1-dependent Localization Of Pkd2 To Mitotic Spindlesmentioning

confidence: 99%

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PKD2 Interacts and Co-localizes with mDia1 to Mitotic Spindles of Dividing Cells

Rundle

Gorbsky

Tsiokas

2004

Journal of Biological Chemistry

110

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Mutations in pkd2 result in the type 2 form of autosomal dominant polycystic kidney disease, which accounts for ϳ15% of all cases of the disease. PKD2, the protein product of pkd2, belongs to the transient receptor potential superfamily of cation channels, and it can function as a mechanosensitive channel in the primary cilium of kidney cells, an intracellular Ca 2؉ release channel in the endoplasmic reticulum, and/or a nonselective cation channel in the plasma membrane. We have identified mDia1/Drf1 (mammalian Diaphanous or Diaphanous-related formin 1 protein) as a PKD2-interacting protein by yeast two-hybrid screen. mDia1 is a member of the RhoA GTPase-binding formin homology protein family that participates in cytoskeletal organization, cytokinesis, and signal transduction. We show that mDia1 and PKD2 interact in native and in transfected cells, and binding is mediated by the cytoplasmic C terminus of PKD2 binding to the mDia1 N terminus. The interaction is more prevalent in dividing cells in which endogenous PKD2 and mDia1 co-localize to the mitotic spindles. RNA interference experiments reveal that endogenous mDia1 knockdown in HeLa cells results in the loss of PKD2 from mitotic spindles and alters intracellular Ca 2؉ release. Our results suggest that mDia1 facilitates the movement of PKD2 to a centralized position during cell division and has a positive effect on intracellular Ca 2؉ release during mitosis. This may be important to ensure equal segregation of PKD2 to the daughter cell to maintain a necessary level of channel activity. Alternatively, PKD2 channel activity may be important in the cell division process or in cell fate decisions after division.

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Section: Mdia1-dependent Localization Of Pkd2 To Mitotic Spindlessupporting

confidence: 68%

mentioning

confidence: 87%

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PKD2 Interacts and Co-localizes with mDia1 to Mitotic Spindles of Dividing Cells

Rundle

Gorbsky

Tsiokas

2004

Journal of Biological Chemistry

110

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“…The identities of the signaling components important for wing hair orientation remain to be determined. Noteworthy is the observation that mutations in vertebrate diaphanous, another extensively characterized effector of Rho that is a member of the formin-homology family of proteins (Watanabe et al 1997), lead to the autosomal dominant hearing-loss syndrome DFNA1 (Lynch et al 1997). In mammalian cells, Dia1 has been found to work in concert with Rok to induce stress fibers in transfected fibroblasts (Watanabe et al 1999).…”

Section: Planar Polaritymentioning

confidence: 99%

Role of Rho family GTPases in epithelial morphogenesis

Aelst¹,

Symons²

2002

Genes Dev.

213

184

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“…Other actin-binding proteins that are associated with deafness include myosin VIIA (USH1B, DFNB2 and DFNA11) (Weil et al 1995 ;Tamagawa et al 1996) and diaphanous (DFNA1) (Lynch et al 1997). …”

Section: mentioning

confidence: 99%

2E4/Kaptin (KPTN) – a candidate gene for the hearing loss locus, DFNA4

Bearer

Chen

et al. 2000

Annals of Human Genetics

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Stereocilia of the inner ear play an integral role in the mechanotransduction of sound. Their structural support is derived from actin filaments and actin-binding proteins. We have identified a novel actin-binding protein, 2E4-kaptin (KPTN), which appears to be involved in this structural network. Using double label immunofluorescence, we now show that KPTN extends beyond the barbed ends of actin filaments at the tips of stereocilia, and using cloned human cDNA, we mapped KPTN to chromosome 19q13.4. A combination of FISH, radiation hybrid mapping and YAC screening localized KPTN between markers D19S412 and NIB1805, making this gene an excellent functional and positional candidate for DFNA4, a form of autosomal dominant non-syndromic hearing loss. We identified a second family with inherited deafness that also maps to the DFNA4 region. To screen KPTN for deafness-causing mutations, we first determined its genomic structure and then completed a mutational analysis by direct sequencing and SSCP in affected family members. Although no deafness-causing mutations were identified in the coding region, KPTN remains an excellent candidate gene for hearing loss ; by synteny, its murine orthologue also remains a candidate gene for the Nijmegan waltzer (nv) mouse mutant, which has vestibular defects and a variable sensorineural hearing loss. Mechanotransduction of hearing is mediated through hair cells of the sensory epithelium of the inner ear (Hudspeth, 1997). These cells lie below the tectorial membrane, which oscillates in response to sound waves, displacing stereocilia and opening gated ion channels to give rise to an electrical signal. Each hair cell has a unique complement of stereocilia, varying in length and

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Nonsyndromic Deafness DFNA1 Associated with Mutation of a Human Homolog of the Drosophila Gene diaphanous

Cited by 402 publications

References 31 publications

PKD2 Interacts and Co-localizes with mDia1 to Mitotic Spindles of Dividing Cells

PKD2 Interacts and Co-localizes with mDia1 to Mitotic Spindles of Dividing Cells

Role of Rho family GTPases in epithelial morphogenesis

2E4/Kaptin (KPTN) – a candidate gene for the hearing loss locus, DFNA4

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