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 1,2 . 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.

Filamin-regulated F-actin Assembly Is Essential for Morphogenesis and Controls Phototaxis in Dictyostelium

“…Furthermore, they are involved in signal transduction and interactions with several components of the NF B pathway and components of adhesion complexes, and the small GTPases RhoA, Rac1, Cdc42, and RalA have been reported to also interact with filamins (15,16). Mutations in the human FLNa gene are responsible for congenital malformations affecting multiple organ systems, presumably because of defective cell migration during embryonal development (17,18), and mutations in the FLNb gene cause skeletal malforma-tions (16,19). In Drosophila, filamin mutations affect oogenesis (20).…”

Filamin structure, function and mechanics: are altered filamin-mediated force responses associated with human disease?

“…In parallel, loss-of-function mutations in FLNB are associated with spondylocarpotarsal synostosis syndrome, and dominant gain-of-function missense mutations are associated with the atelosteogenesis group of skeletal malformation (Krakow et al 2004). The clinical distinction, mode of inheritance of the FLN gain-of-function phenotypes, FLN expression and increased actin binding activity of disease-associated mutant FLNs are consistent with a gain/alteration of FLN function mechanism for these disorders (Robertson et al 2003;Sawyer et al 2009;Clark et al 2009). FLNB is highly localised along the human growth plate and in the cartilage of developing vertebrae (Krakow et al 2004), though the role that FLN plays in bone development remains unclear.…”

“…Lossof-function mutations in X-linked FLNA are associated with the brain malformation disorder, periventricular nodular heterotopia (PH) , typically male embryonic lethal and underlying abnormal neuronal migration during brain development causing seizures in females (Moro et al 2002). FLNA missense mutations are associated with the otopalatodigital spectrum malformation disorders (OPD) primarily affecting skeletal development, clinically distinct from PH (Robertson et al 2003). In parallel, loss-of-function mutations in FLNB are associated with spondylocarpotarsal synostosis syndrome, and dominant gain-of-function missense mutations are associated with the atelosteogenesis group of skeletal malformation (Krakow et al 2004).…”

A Japanese case of oto-palato-digital syndrome type II: an apparent lack of phenotype–genotype correlation

“…FLNA is a gene encoding an actin-binding protein, and mutations in this gene have been detected in patients with Melnick-Needles syndrome or frontometaphyseal dysplasia in addition to OPD I and OPD II. However, it is not clear why mutations in the same gene results in different clinical entities (Robertson et al 2003;Robertson 2005). Here, we report on a 12-year-old boy with severe OPD II manifestations whose mutation in FLNA was identical to that of an OPD I patient.…”

“…Robertson et al (2003) demonstrated that OPD II is caused by mutations in the coding region of the filamin A gene (FLNA; OMIM: 300017). FLNA is a gene encoding an actin-binding protein, and mutations in this gene have been detected in patients with Melnick-Needles syndrome or frontometaphyseal dysplasia in addition to OPD I and OPD II.…”