title: Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.
abstract: 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.
authors.affiliation: Weatherall Institute of Molecular Medicine, Room 304, The John Radcliffe, Headley Way, Oxford OX3 9DS, UK. stephen.robertson@stonebow.otago.ac.nz
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Stephen R F
authors.initials: SR
authors.lastname: Twigg
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sutherland-Smith
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gorlin
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Kenwrick
authors.forename: Chong A
authors.initials: CA
authors.lastname: Kim
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Ruth
authors.initials: R
authors.lastname: Newbury-Ecob
authors.forename: Karen H
authors.initials: KH
authors.lastname: Orstavik
authors.forename: Oliver W J
authors.initials: OW
authors.lastname: Quarrell
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Shears
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.forename: John
authors.initials: J
authors.lastname: Kendrick-Jones
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D003285:Contractile Proteins / Q000235:genetics*; D003599:Cytoskeleton / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D064448:Filamins; D008040:Genetic Linkage; D006801:Humans; D007438:Introns; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013577:Syndrome; D014018:Tissue Distribution
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins