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PubMed1983

Cytoskeletal components of the vertebrate neuromuscular junction: vinculin, alpha-actinin, and filamin.

We have used immunocytochemical methods to investigate the cytoskeletal constituents of the vertebrate neuromuscular junction. Specific, affinity-purified antibodies to three cytoskeletal proteins, vinculin, alpha-actinin, and filamin, bound to neuromuscular junctions in sections of normal rat, mouse, chick, and Xenopus muscles. All three antibodies bound to the synaptic regions of denervated rat muscle fibers, indicating that the proteins recognized by these antibodies are associated with postsynaptic structures. The three proteins are present at the neuromuscular junction in muscle fibers of embryonic and neonatal animals, and therefore, may play an important role in its differentiation.

Actinin↗
PubMed2006

Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations.

Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).

Abnormalities, Multiple↗
PubMed2001

Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females.

Periventricular heterotopia (PH) is a human neuronal migration disorder in which many neurons destined for the cerebral cortex fail to migrate. Previous analysis showed heterozygous mutations in the X-linked gene filamin 1 (FLN1), but examined only the first six (of 48) coding exons of the gene and hence did not assess the incidence and functional consequences of FLN1 mutations. Here we perform single-strand conformation polymorphism (SSCP) analysis of FLN1 throughout its entire coding region in six PH pedigrees, 31 sporadic female PH patients and 24 sporadic male PH patients. We detected FLN1 mutations by SSCP in 83% of PH pedigrees and 19% of sporadic females with PH. Moreover, no PH females (0/7 tested) with atypical radiographic features showed FLN1 mutations, suggesting that other genes may cause atypical PH. Surprisingly, 2/24 males analyzed with PH (9%) also carried FLN1 mutations. Whereas FLN1 mutations in PH pedigrees caused severe predicted loss of FLN1 protein function, both male FLN1 mutations were consistent with partial loss of function of the protein. Moreover, sporadic female FLN1 mutations associated with PH appear to cause either severe or partial loss of function. Neither male could be shown to be mosaic for the FLN1 mutation in peripheral blood lymphocytes, suggesting that some neurons in the intact cortex of PH males may be mutant for FLN1 but migrate adequately. These results demonstrate the sensitivity and specificity of DNA testing for FLN1 mutations and have important functional implications for models of FLN1 protein function in neuronal migration.

Abnormalities, Multiple↗
PubMed2006

Cardiac malformations and midline skeletal defects in mice lacking filamin A.

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.

Animals↗
PubMed2006

Mutation in filamin A causes periventricular heterotopia, developmental regression, and West syndrome in males.

PURPOSE: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome. METHODS: The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing. RESULTS: Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrhythmia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene. CONCLUSIONS: The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.

Brain Diseases↗
PubMed2004

Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site.

The Ras-mitogen-activated protein (Ras-MAP) kinase pathway regulates various cellular processes, including gene expression, cell proliferation, and survival. Ribosomal S6 kinase (RSK), a key player in this pathway, modulates the activities of several cytoplasmic and nuclear proteins via phosphorylation. Here we report the characterization of the cytoskeletal protein filamin A (FLNa) as a membrane-associated RSK target. We show that the N-terminal kinase domain of RSK phosphorylates FLNa on Ser(2152) in response to mitogens. Inhibition of MAP kinase signaling with UO126 or mutation of Ser(2152) to Ala on FLNa prevents epidermal growth factor (EGF)-stimulated phosphorylation of FLNa in vivo. Furthermore, phosphorylation of FLNa on Ser(2152) is significantly enhanced by the expression of wild-type RSK and antagonized by kinase-inactive RSK or specific reduction of endogenous RSK. Strikingly, EGF-induced, FLNa-dependent migration of human melanoma cells is significantly reduced by UO126 treatment. Together, these data provide substantial evidence that RSK phosphorylates FLNa on Ser(2152) in vivo. Given that phosphorylation of FLNa on Ser(2152) is required for Pak1-mediated membrane ruffling, our results suggest a novel role for RSK in the regulation of the actin cytoskeleton.

Amino Acid Sequence↗
PubMed2005

FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin A-mediated manner.

FOXC1 mutations underlie Axenfeld-Rieger syndrome, an autosomal dominant disorder that is characterized by a spectrum of ocular and nonocular phenotypes and results in an increased susceptibility to glaucoma. Proteins interacting with FOXC1 were identified in human nonpigmented ciliary epithelial cells. Here we demonstrate that FOXC1 interacts with the actin-binding protein filamin A (FLNA). In A7 melanoma cells possessing elevated levels of nuclear FLNA, FOXC1 is unable to activate transcription and is partitioned to an HP1alpha, heterochromatin-rich region of the nucleus. This inhibition is mediated through an interaction between FOXC1 and the homeodomain protein PBX1a. In addition, we demonstrate that efficient nuclear and subnuclear localization of PBX1 is mediated by FLNA. Together, these data reveal a mechanism by which structural proteins such as FLNA can influence the activity of a developmentally and pathologically important transcription factor such as FOXC1. Given the resemblance of the skeletal phenotypes caused by FOXC1 loss-of-function mutations and FLNA gain-of-function mutations, this inhibitory activity of FLNA on FOXC1 may contribute to the pathogenesis of FLNA-linked skeletal disorders.

Cell Fractionation↗
PubMed2006

Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins.

beta-Arrestins (betaarr) are multifunctional adaptor proteins that can act as scaffolds for G protein-coupled receptor activation of mitogen-activated protein kinases (MAPK). Here, we identify the actin-binding and scaffolding protein filamin A (FLNA) as a betaarr-binding partner using Son of sevenless recruitment system screening, a classical yeast two-hybrid system, coimmunoprecipitation analyses, and direct binding in vitro. In FLNA, the betaarr-binding site involves tandem repeat 22 in the carboxyl terminus. betaarr binds FLNA through both its N- and C-terminal domains, indicating the presence of multiple binding sites. We demonstrate that betaarr and FLNA act cooperatively to activate the MAPK extracellular signal-regulated kinase (ERK) downstream of activated muscarinic M1 (M1MR) and angiotensin II type 1a (AT1AR) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of betaarr-ERK2 complex formation by FLNA. In Hep2 cells, stimulation of M1MR or AT1AR results in the colocalization of receptor, betaarr, FLNA, and active ERK in membrane ruffles. Reduction of endogenous levels of betaarr or FLNA and a catalytically inactive dominant negative MEK1, which prevents ERK activation, inhibit membrane ruffle formation, indicating the functional requirement for betaarr, FLNA, and active ERK in this process. Our results indicate that betaarr and FLNA cooperate to regulate ERK activation and actin cytoskeleton reorganization.

Actins↗
PubMed2005

A filamin A splice mutation resulting in a syndrome of facial dysmorphism, periventricular nodular heterotopia, and severe constipation reminiscent of cerebro-fronto-facial syndrome.

BACKGROUND: Mutations of the filamin A locus (FLNA) on Xq28 have been established in girls with periventricular nodular heterotopia and in patients with otopalatodigital and overlapping phenotypes, the pathogenesis of these phenotypes being thought to be quite distinct. To date only six male cases of periventricular nodular heterotopia (PVNH) have been reported and these almost invariably associated with severe neurological signs. METHODS AND RESULTS: We report a new phenotype of male PVNH, with relatively normal development, no epilepsy or other neurological abnormality, severe constipation, and facial dysmorphism and without a discernible skeletal phenotype. This phenotype is associated with a splice site mutation in FLNA c.1923C>T, resulting in the generation of both normal and aberrant mRNA. CONCLUSIONS: We postulate that the patient retains enough FLNA function to avoid the usual lethality associated with loss of function mutations in males and suggest that the severe constipation may be a clue to the molecular aetiology of other X linked conditions associated with severe constipation.

Abnormalities, Multiple↗
PubMed2006

Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy.

BACKGROUND: Myxomatous dystrophy of the cardiac valves affects approximately 3% of the population and remains one of the most common indications for valvular surgery. Familial inheritance has been demonstrated with autosomal and X-linked transmission, but no specific molecular abnormalities have been documented in isolated nonsyndromic forms. We have investigated the genetic causes of X-linked myxomatous valvular dystrophy (XMVD) previously mapped to chromosome Xq28. METHODS AND RESULTS: A familial and genealogical survey led us to expand the size of a large, previously identified family affected by XMVD and to refine the XMVD locus to a 2.5-Mb region. A standard positional cloning approach identified a P637Q mutation in the filamin A (FLNA) gene in all affected members. Two other missense mutations (G288R and V711D) and a 1944-bp genomic deletion coding for exons 16 to 19 in the FLNA gene were identified in 3 additional, smaller, unrelated families affected by valvular dystrophy, which demonstrates the responsibility of FLNA as a cause of XMVD. Among carriers of FLNA mutation, the penetrance of the disease was complete in men and incomplete in women. Female carriers could be mildly affected, and the severity of the disease was highly variable among mutation carriers. CONCLUSIONS: Our data demonstrate that FLNA is the first gene known to cause isolated nonsyndromic MVD. This is the first step to understanding the pathophysiological mechanisms of the disease and to defining pathways that may lead to valvular dystrophy. Screening for FLNA mutations could be important for families affected by XMVD to provide adequate follow-up and genetic counseling.

Adolescent↗
PubMed2005

The structure of the GPIb-filamin A complex.

Filamin A (FLNa), a dimeric actin cross-linking and scaffold protein with numerous intracellular binding partners, anchors the platelet adhesion glycoprotein (GP) Ib-IX-V receptor to actin cytoskeleton. We mapped the GPIbalpha binding site to a single domain of FLNa and resolved the structure of this domain and its interaction complex with the corresponding GPIbalpha cytoplasmic domain. This is the first atomic structure of this class of membrane glycoprotein-cytoskeleton connection. GPIbalpha binds in a groove formed between the C and D beta strands of FLNa domain 17. The interaction is strikingly similar to that between the beta7 integrin tail and a different FLNa domain, potentially defining a conserved motif for FLNa binding. Nevertheless, the structures also reveal specificity of the interfaces, which explains different regulatory mechanisms. To verify the topology of GPIb-FLNa interaction we also purified the native complex from platelets and showed that GPIb interacts with the C-terminus of FLNa, which is in accordance with our biochemical and structural data.

Contractile Proteins↗
PubMed2003

A search for doxycycline-dependent mutations that increase Drosophila melanogaster life span identifies the VhaSFD, Sugar baby, filamin, fwd and Cctl genes.

BACKGROUND: A P-type transposable element called PdL has been engineered with a doxycycline-inducible promoter directed out through the 3' end of the element. Insertion of PdL near the 5' end of a gene often yields doxycycline-dependent overexpression of that gene and a mutant phenotype. This functional genomics strategy allows for efficient screening of large numbers of genes for overexpression phenotypes. RESULTS: PdL was mobilized to around 10,000 new locations in the Drosophila melanogaster genome and used to search for genes that would extend life span when overexpressed. Six lines were identified in which there was a 5-17% increase in life span in the presence of doxyxcycline. The mutations were molecularly characterized and in each case a gene was found to be overexpressed using northern blots. Two genes did not have previously known phenotypes and are implicated in membrane transport: VhaSFD encodes a regulatory subunit of the vacuolar ATPase proton pump (H+-ATPase), whereas Sugar baby (Sug) is related to a maltose permease from Bacillus. Three PdL mutations identified previously characterized genes: filamin encodes the homolog of an actin-polymerizing protein that interacts with presenilins. four wheel drive (fwd) encodes a phosphatidylinositol-4-kinase (PI 4-kinase) and CTP:phosphocholine cytidylyltransferase-l (Cctl) encodes the rate-limiting enzyme in phosphatidylcholine synthesis. Finally, an apparently novel gene (Red herring, Rdh) was found in the first intron of the encore gene. CONCLUSIONS: Screening for conditional mutations that increase Drosophila life span has identified genes implicated in membrane transport, phospholipid metabolism and signaling, and actin cytoskeleton organization.

1-Phosphatidylinositol 4-Kinase↗
PubMed2006

Filamin A is required for T cell activation mediated by protein kinase C-theta.

Induction of T cell responses following engagement of the Ag-specific TCR depends on TCR-initiated rearrangements of the cellular actin cytoskeleton and highly coordinated and tightly regulated interactions and of diverse intracellular signaling proteins. In this study, we show that filamin A (FLNa), an actin-binding and signal mediator scaffolding protein, is required for T cell activation. Following Ag stimulation, FLNa was recruited to the T cell-APC contact area, where it colocalized with protein kinase C-theta (PKCtheta). Depletion of FLNa by RNA interference did not affect TCR-induced early tyrosine phosphorylation or actin polymerization but, nevertheless, resulted in impaired IL-2 expression by human primary T cells and reduced activation of NF-kappaB, AP-1, and NFAT reporter genes in transfected T cells. TCR stimulation induced stable physical association of FLNa with PKCtheta. Furthermore, the TCR/CD28-induced membrane translocation of PKCtheta was inhibited in FLNa-depleted T cells. These results reveal novel role for FLNa in the TCR/CD28 signaling pathway leading to transcription factor activation and IL-2 production, and suggest that this role is mediated, in part, through the inducible interaction of FLNa with PKCtheta.

Antigen-Presenting Cells↗
PubMed1992

[ELISA for detection of anti-filamin antibody in sera from patient with myasthenia gravis].

The activity of anti-filamin antibody was determined in sera from 128 patients with myasthenia gravis (MG) by enzyme-linked immunosorbent assay (ELISA). The positive rate was 77.34%. No correlation was observed between anti-F-ab and nAchRab and CAEab. The antibody-absorbtion test were positive. The result demonstrated that anti-F-ab may play some role in the pathology of MG. The clinical use of ELISA for detection of anti-F-ab may help to diagnose MG.

Adolescent↗
PubMed1986

Localization of a filamin-like protein in glia of the chick central nervous system.

Monoclonal antibody 5E10 binds to Muller cells in the chick retina and radial glia in the optic tectum. Biochemical and immunohistochemical experiments indicate that the 5E10 antigen is related to, but may not be identical to, filamin, a high-molecular-weight, actin-binding protein. Developmental studies show that the 5E10 antigen is present in all neuroepithelial cells very early in development, but disappears by about Embryonic Day 10. These results suggest that neurons developmentally regulate not only the type of intermediate filament proteins they express, switching from vimentin to neurofilaments, but also the type of actin-binding proteins.

Animals↗
PubMed1993

Further characterization of the alpha-actinin-actin interface and comparison with filamin-binding sites on actin.

The interaction between alpha-actinin and actin was further characterized using natural and synthetic peptides of actin together with anti-actin antibodies of known specificity. We demonstrated that two alpha-actinin binding sequences on actin are located within residues 112-125 and 360-372. Each peptide was shown to directly bind alpha-actinin and was able to dissociate the alpha-actinin-actin complex using solid phase binding assays and cosedimentation experiments. Taking into account the three-dimensional structure of actin (Kabsch, W., Mannherz, H. G., Suck, D., Pai, E. F., and Holmes, K. C. (1990) Nature 347, 37-44), we postulate that these two segments, proximal in the actin structure, are part of the same site. In addition, we compared these two segments with those recently found for filamin (Méjean, C., Lebart, M. C., Boyer, M., Roustan, C., and Benyamin, Y. (1992) Eur. J. Biochem. 209, 555-562), Egan, S., Stewart, M., Stossel, T. P., Kwiatkowski, D. J., and Hartwig, J. H. (1990) J. Cell Biol. 111, 1089-1105), and concluded that the two actin-binding proteins interact with closely spaced or overlapping but not identical sequences of actin subdomain 1.

Actinin↗