Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1038/ng1119

Type

Journal article

Journal

Nat Genet

Publication Date

04/2003

Volume

33

Pages

487 - 491

Keywords

Abnormalities, Multiple, Alleles, Amino Acid Sequence, Base Sequence, Chromosome Mapping, Chromosomes, Human, X, Contractile Proteins, Cytoskeleton, DNA Mutational Analysis, Female, Filamins, Genetic Linkage, Humans, Introns, Male, Microfilament Proteins, Models, Genetic, Models, Molecular, Molecular Sequence Data, Mutation, Phylogeny, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Sequence Homology, Amino Acid, Signal Transduction, Syndrome, Tissue Distribution