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Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans 总被引:18,自引:0,他引:18
Robertson SP Twigg SR Sutherland-Smith AJ Biancalana V Gorlin RJ Horn D Kenwrick SJ Kim CA Morava E Newbury-Ecob R Orstavik KH Quarrell OW Schwartz CE Shears DJ Suri M Kendrick-Jones J Wilkie AO;OPD-spectrum Disorders Clinical Collaborative Group 《Nature genetics》2003,33(4):487-491
Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development. 相似文献
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Gissen P Johnson CA Morgan NV Stapelbroek JM Forshew T Cooper WN McKiernan PJ Klomp LW Morris AA Wraith JE McClean P Lynch SA Thompson RJ Lo B Quarrell OW Di Rocco M Trembath RC Mandel H Wali S Karet FE Knisely AS Houwen RH Kelly DA Maher ER 《Nature genetics》2004,36(4):400-404
ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion. 相似文献
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Crow YJ Leitch A Hayward BE Garner A Parmar R Griffith E Ali M Semple C Aicardi J Babul-Hirji R Baumann C Baxter P Bertini E Chandler KE Chitayat D Cau D Déry C Fazzi E Goizet C King MD Klepper J Lacombe D Lanzi G Lyall H Martínez-Frías ML Mathieu M McKeown C Monier A Oade Y Quarrell OW Rittey CD Rogers RC Sanchis A Stephenson JB Tacke U Till M Tolmie JL Tomlin P Voit T Weschke B Woods CG Lebon P Bonthron DT Ponting CP Jackson AP 《Nature genetics》2006,38(8):910-916
Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation. 相似文献
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