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

Stephen P. Robertson, Stephen R F Twigg, Andrew J. Sutherland-Smith, Valérie Biancalana, Robert J. Gorlin, Denise Horn, Susan J. Kenwrick, Chong A. Kim, Eva Morava, Ruth Newbury-Ecob, Karen H. Ørstavik, Oliver W J Quarrell, Charles E. Schwartz, Deborah J. Shears, Mohnish Suri, John Kendrick-Jones, C. Bacino, K. Becker, J. Clayton-Smith, M. Giovannucci-UzielliD. Goh, D. Grange, M. Krajewska-Welasek, D. Lacombe, C. Morris, S. Odent, R. Savarirayan, R. Stratton, A. Superti-Furga, A. Verloes, J. Vigneron, W. Wilcox, R. Winter, K. Young, O. M. Wilkie

    Research output: Contribution to journalArticlepeer-review


    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 messengers1,2. 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.
    Original languageEnglish
    Pages (from-to)487-491
    Number of pages4
    JournalNature Genetics
    Issue number4
    Publication statusPublished - 1 Apr 2003


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