Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.

Authors: 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  Wilkie, Andrew O M 
Citation: Robertson SP, etal., Nat Genet. 2003 Apr;33(4):487-91. Epub 2003 Mar 3.
Pubmed: (View Article at PubMed) PMID:12612583
DOI: Full-text: DOI:10.1038/ng1119

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.

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CRRD Object Information
CRRD ID: 1598954
Created: 2007-01-05
Species: All species
Last Modified: 2007-01-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.