Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have determined the exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280 (filamin), a ubiquitous protein that plays an important role in the mechanochemical activities of cells through its association with actin filaments and membrane components. The gene is composed of 47 exons spanning approximately 26 kb. The first and part of the second exon are untranslated. The actin-binding domain at the N-terminus is encoded by exons 2 to 5. The 96-amino-acid repeats corresponding to the elongated rod backbone of the protein are encoded by the remaining 42 exons: size, location, and boundaries of the exons cannot be easily correlated with the repeated structure, while sequences interrupting the repeats (the two hinge segments preceding repeats 16 and 24 and the 8-amino-acid (aa) segment interrupting the 15th repeat) were encoded by separate exons, suggesting that they may be recent additions to the X-linked protein. The 8-aa segment is encoded by exon 29, which is alternatively spliced.
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PMID:The exon-intron organization of the human X-linked gene (FLN1) encoding actin-binding protein 280. 808 19

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked disorder characterized by contractures, progressive muscle weakness and cardiomyopathy. The emerin gene, located in human Xq28, is approximately 2 kb in length, is composed of 6 exons and falls within a 219-kb region that has been completely sequenced. Immediately centromeric to emerin is the 26-kb filamin gene (FLN1), composed of 48 exons and encoding the actin-binding protein 280 (refs 7,8). Flanking this 48-kb FLN1/emerin region are two large inverted repeats, each 11.3 kb, that exhibit > 99% sequence identity. The high level of genomic detail in this region allowed us to characterize the first complete emerin gene deletion mutation that also involved a partial duplication of the nearby FLN1 gene. This rearrangement could be explained by mispairing of the large inverted repeats, followed by double recombination among one set of mispaired repeats and internal sequences. Furthermore, our characterization of this rare DNA rearrangement revealed a more common result of the mispairing of these large inverted repeats--recombination contained within the inverted repeats leading to the maintenance of repeat sequence homogeneity and inversion of the 48-kb FLN1/emerin region. The presence of this frequent inversion, found in the heterozygous state in 33% of females, helps to explain the discrepancies observed between the genetic and physical map distances in this region of the X chromosome. It also illustrates the biological insights which can be gleaned by sequencing the human genome.
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PMID:Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats. 914 Mar 86

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked disorder characterized by contractures, progressive weakness and cardiomyopathy. EMD is caused by mutations in the 2 kb emerin gene that is located within human Xq28. Emerin is immediately distal to the 26 kb filamin gene, and flanking the filamin-emerin region are two large inverted repeats. This entire region previously has been found to be inverted in approximately 20% of X chromosomes, presumably mediated by the inverted repeats. Only one complete emerin deletion has been reported previously. It was found to be due to a complex rearrangement involving the inverted repeats which partially duplicated filamin. We report here two additional EMD patients who have large deletions of 20 and 34 kb, respectively. Unlike the previously reported deletion, these deletions appear to be simple deletions, with each breakpoint junction showing only 2 bp of overlap, suggesting an end-joining mechanism. However, the two deletions were found on each of the two inverted backgrounds. The 20 kb deletion includes the entire emerin gene and extends well into most of the distal inverted repeat. In contrast, the 34 kb deletion occurs on the inverted X chromosome and extends centromeric, well beyond the proximal inverted repeat. In addition, at least three nearby putative genes detected by previous sequence analysis are deleted among these patients but without obvious deviation from a typical EMD phenotype. Similarly to the previously reported deletion, filamin remains intact in these two deletions. All three deletions involve distinct breakpoints within the 4.7 kb filamin-emerin intergenic region, suggesting that loss of filamin is a lethal event. Thus, the close proximity of filamin to emerin may place constraints upon potential emerin deletions and probably accounts for the rarity of complete emerin deletions in EMD patients.
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PMID:Emerin deletions occurring on both Xq28 inversion backgrounds. 938 14

Mutations in the genes that encode filamin-1, Lis1 and doublecortin are responsible for X-linked lissencephaly in man, whereas mutations in the genes that encode Cdk5, its activator p35 and the reelin-signaling pathway disturb migration and architectonic development in mice. To understand the action of genes that control neuronal migration and the phenotype of corresponding defects, it might be as important to consider the positioning of the nucleus as it is to consider the guidance of the leading process.
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PMID:Potential mechanisms of mutations that affect neuronal migration in man and mouse. 1082 84

This annotation describes the clinical and pathological features of several conditions believed to result from a primary defect in cell migration which include the lissencephalies, pachygria, polymicrogyrias, and focal cortical dysplasia. A variety of factors must be considered in pathogeneses, including cellular proliferation, cell death, post-migrational intracortical growth and development, axonogenesis and dendritogenesis. At least two distinct types of lissencephaly exist. Classic (also known as Type I) lissencephaly is the prototypic pattern being seen in autosomal dominant Miller-Dieker syndrome, in addition to autosomal recessive and X-linked forms. The Miller-Dieker syndrome locus (LIS-1) encodes the platelet activating factor acetylhydrolase-1, beta1 subunit. The gene for an X-linked form of lissencephaly (XLIS) encodes a protein called doublecortin. Cobblestone (type II) lissencephaly is most commonly seen in patients with the Walker-Warburg syndrome, and also occurs in a group of disorders associated with congenital muscular dystrophy, including Finnish 'muscle-eye-brain' disease and Fukuyama muscular dystrophy. Controversy exits as to whether polymicrogyria is a malformation or a disruption of development. The answer is likely both. Polymicrogyria is believed to arise from defects occurring between 17 and 25 or 26 weeks gestation. Heterotopia can be sporadic, inherited as a simple Mendelian trait, or may be part of a more complex syndrome being characterized by collections of disorganized grey matter in inappropriate places. X-linked periventricular heterotopia syndrome is caused by mutations in filamin-1. In addition to those described above, many other syndromes show lissencephaly, pachygyria and polymicrogyria and many cases are not easily classified into any particular syndrome.
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PMID:Cell migration and cerebral cortical development. 1129 98

Periventricular heterotopia (PVH) are collections of neurons and glia heterotopically located adjacent to the ventricles. The pathogenesis of periventricular heterotopia is believed to be a failure of cells to migrate from the ventricular zone. Mutations in filamin-1 (FLN1) have recently been identified as a genetic defect that results in an X-linked dominant form of PVH. In addition to this X-linked form, PVH may be found sporadically or occasionally as part of other syndromes. The pathogenesis(es) of PVH has not been entirely elucidated for patients with or without FLN1 mutation. In an attempt to better understand the pathogenesis of PVH, we examined 5 fetuses (gestational ages 21 to 34 wk), 3 females and 2 males, with PVH. Neuropathologic examination of these 5 fetuses revealed several to multiple periventricular nodules. No case showed the extensive periventricular heterotopia most commonly found in females with FLN1 mutations. By immunohistochemistry, neurofilament-positive cells were identified within the PVH in 3 of 5 cases and glial fibrillary acidic protein-positive cells surrounded the nodules in all 5 cases, but positive cells were only found within the nodules of 3 cases. Surprisingly, small collections of CD68-positive macrophages were found at the base of the nodules in 4 of the 5 cases. Moreover, in all cases, the radial glia highlighted with vimentin, showed disorganization specifically around the nodules. These data suggest that at least one pathogenesis for PVH is a disruption of the radial glial organization, resulting in a failure of cells to migrate from the ventricular zone.
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PMID:Periventricular heterotopia may result from radial glial fiber disruption. 1155 42

Aicardi syndrome affects only females and has been hypothesized to be an X-linked dominant male-lethal disorder. Because no familial cases can be studied for genetic linkage analysis, the mutated gene has remained elusive. With the goal of selecting genes for mutation analysis by a functional candidate approach, a detailed pathologic analysis of two brains from deceased Aicardi syndrome patients was performed. The presence of micrencephaly, absent or hypoplastic corpus callosum, polymicrogyria, heterotopia, ventriculomegaly, intracerebral cyst, and intracytoplasmic eosinophilic inclusions was confirmed in glial fibrillary acidic protein-positive astrocytes in the cortex and heterotopias, but not in white matter. The inclusions demonstrated strong immunolabeling with antibodies to filamin and vimentin but weak labeling with antibodies to proteins S100 and microtubule-associated protein 1. These findings suggested that an underlying defect in the cytoskeleton, which involves filamin, may cause this condition. Because the filamin A gene in Xq28 is mutated in another disorder with heterotopia, familial bilateral periventricular heterotopia, mutation analysis of filamin A in Aicardi syndrome patients was pursued. No mutations were found, and the full-length protein was expressed in both brain samples. Future studies will focus on investigation of X-linked genes that may affect function of filamin or other cytoskeletal proteins.
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PMID:Presence of filamin in the astrocytic inclusions of Aicardi syndrome. 1473 43

We report here on the first case of a child with bilateral periventricular nodular heterotopia (PNH) and Williams syndrome. Fluorescent in situ hybridization (FISH) analyses demonstrated a deletion of the elastin gene in the Williams syndrome critical region (WSCR). Further mapping by loss of heterozygosity analysis both by microsatellite marker and SNP profiling demonstrated a 1.5 Mb deletion beyond the telomeric end of the typical WSCR. No mutations were identified in the X-linked filamin-A gene (the most common cause of PNH). These findings suggest another dominant PNH disorder along chromosome 7q11.23.
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PMID:Periventricular nodular heterotopia and Williams syndrome. 1669 86

Frontometaphyseal dysplasia is an X-linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X-linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.
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PMID:Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity. 1683 13

Several disorders characterized primarily by anomalies of the skeleton have recently been shown to be caused by mutations in the X-linked gene, FLNA. One of these conditions, the Melnick-Needles syndrome exhibits a phenotype that shares overlap with that of serpentine fibula-polycystic kidney syndrome and the autosomal dominant condition, Hajdu-Cheney syndrome. Here, we describe three individuals with these diagnoses. The individual with serpentine fibula-polycystic kidney syndrome, the fifth case reported in the literature, exhibited wormian bones which further expands the phenotypic spectrum for this condition and extends the overlap with Hajdu-Cheney syndrome. All three members of the filamin gene family, FLNA, and its functionally related paralogues, FLNB and FLNC, were screened for pathogenic mutations in all three individuals. We found a mutation in FLNA in the individual with Melnick-Needles syndrome, but no pathogenic variants in any filamin gene in the two individuals with Hajdu-Cheney syndrome and serpentine fibula-polycystic kidney syndrome. Clinical and molecular evidence indicates that Melnick-Needles syndrome is aetiologically distinct from Hajdu-Cheney syndrome and serpentine fibula-polycystic kidney syndrome, but these two latter conditions share many clinical similarities and may prove to be allelic to one another.
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PMID:Phenotypic overlap in Melnick-Needles, serpentine fibula-polycystic kidney and Hajdu-Cheney syndromes: a clinical and molecular study in three patients. 1715 11


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