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Nucleotide, Protein, OMIM, Cited in PMC, Books, LinkOut

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

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.

Weatherall Institute of Molecular Medicine, Room 304, The John Radcliffe, Headley
Way, Oxford OX3 9DS, UK. stephen.robertson@stonebow.otago.ac.nz

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.

PMID: 12612583 [PubMed - indexed for MEDLINE]