Cardiac malformations and midline skeletal defects in mice lacking filamin A

Abstract

The X-linked gene filamin A (Flna) encodes a widely expressed actin-binding protein that crosslinks actin into orthogonal networks and interacts with a variety of other proteins including membrane proteins, integrins, transmembrane receptor complexes and second messengers, thus forming an important intracellular signalling scaffold. Heterozygous loss of function of human FLNA causes periventricular nodular heterotopia in females and is generally lethal (cause unknown) in hemizygous males. Missense FLNA mutations underlie a spectrum of disorders affecting both sexes that feature skeletal dysplasia accompanied by a variety of other abnormalities. Dilp2 is an X-linked male-lethal mouse mutation that was induced by N-ethyl-N-nitrosourea. We report here that Dilp2 is caused by a T-to-A transversion that converts a tyrosine codon to a stop codon in the Flna gene (Y2388X), leading to absence of the Flna protein and male lethality because of incomplete septation of the outflow tract of the heart, which produces common arterial trunk. A proportion of both male and female mutant mice have other cardiac defects including ventricular septal defect. In addition, mutant males have midline fusion defects manifesting as sternum and palate abnormalities. Carrier females exhibit milder sternum and palate defects and misshapen pupils. These results define crucial roles for Flna in development, demonstrate that X-linked male lethal mutations can be recovered from ENU mutagenesis screens and suggest possible explanations for lethality of human males hemizygous for null alleles of FLNA.

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

“…Because FlnA deficiency is embryonic lethal in mice (Feng et al, 2006;Hart et al, 2006), mice lacking FlnA in platelets were generated using the Cre-loxP system. FlnA loxP/loxP female mice were bred with erythroid/megakaryocytic-specific GATA1-Cre transgenic male mice.…”

“…1, E and F). defects, and aberrant vascular patterning (Feng et al, 2006;Hart et al, 2006). Because the FLNA gene is located on the X chromosome, we determined whether it conferred survival value to platelets in 6-8-wk-old heterozygous female mice carrying both one WT and one deleted FLNA gene.…”

“…FLNA mutations have been associated with periventricular heterotopia, Ehlers-Danlos Syndrome, or familial cardiac valvular dystrophy (Fox et al, 1998;Robertson et al, 2003;Sheen et al, 2005;Kyndt et al, 2007;Unger et al, 2007). Loss of FlnA in mice results in embryonic lethality caused by pericardiac and visceral hemorrhage, severe cardiac structural defects, and aberrant vascular patterning (Feng et al, 2006;Hart et al, 2006).…”

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

“…MIM Number: *300017 and *603381, respectively). This difference is mirrored in the mouse, where the deletion of the Flna gene causes lethal heart and vascular defects [16,17] while the deletion of the Flnb gene leads to lethal skeletal malformations with bone fusions [18,19]. …”

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

“…The figure was prepared with PYMOL (DeLano 2002) localisation at the membrane (Meyer et al 1998). FLNA null mouse embryonic fibroblasts (Hart et al 2006), neural crest cells (Feng et al 2006) and FLNA missense mutant human fibroblasts show no motility phenotype, whereas downregulation of FLNA expression leads to increased breast tumour cell line motility via a mechanism in which FLNA regulates focal adhesion disassembly in a calpain-dependent manner (Xu et al 2010). Simultaneous knockdown of both FLNA and FLNB, or increased proteasomal degradation of all three FLNs, results in a defect in initiation of HT1080 cell motility and spreading (Baldassarre et al 2009).…”