Actin-Binding Protein (ABP-280) Filamin Gene (FLN) Maps Telomeric to the Color Vision Locus (R/GCP) and Centromeric to G6PD in Xq28

doi:10.1006/geno.1993.1354

Genomics

Volume 17, Issue 2, August 1993, Pages 496-498

https://doi.org/10.1006/geno.1993.1354 Get rights and content

Abstract

Actin-binding protein-280 (ABP-280) is a dimeric actin filament crosslinking protein that promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins. We have mapped the ABP-280 filamin gene (FLN) to Xq28 by Southern blot analysis of somatic cell hybrid lines, by fluorescence in situ hybridization, and through identification of portions of the FLN gene within cosmids and YACs mapped to Xq28. The FLN gene is found within a 200-kb region centromeric to the G6PD locus and telomeric to DSX52 and the color vision locus.

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Somatic mosaicism is well known in disorders where the manifestations are readily seen, e.g. the skin in neurofibromatosis I. In single gene disorders of higher frequency, especially X-linked ones, the frequency of combined germ-line and somatic mosaicism is increasingly being appreciated, e.g. Duchenne Muscular Dystrophy. Cell separation techniques; such as the fluorescence-activated cell sorter (FACS) also detect much somatic mosaicism among blood cells in disorders such as paroxysmal nocturnal hemoglobinuria. Depending on the disorder and the class of mutation, in genes for which there are sufficient numbers of patients studied, 6–20% of cases are due to somatic mutation. This update of my previous review is stimulated by the rapid application of new technologies for the study of DNA variation in disease. The results of these studies implicate somatic mutation in a greater variety of genetic diseases and a wider spectrum of tissues than have previously been shown, including heart and kidney. The classes of mutation have also expanded beyond base pair changes, insertions/deletion (indels), and short tandem repeat mutations to include copy number variants and transposon-mediated mutations. I also briefly discuss previously well-known mosaicism for chromosomal mutations. Genomic sequencing, performed on DNA from blood, shows many mutations which are conclusively somatic in origin. It is still too early to see if there is a different pattern of somatic mutation compared to germ-line mutation. Though the parameters to allow careful quantification are not yet available, it seems that the frequency of gene mutation in embryonic cells is not markedly different than that in the germ line.
Mendelian Inheritance in Man and its online version, OMIM
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Consistent with the Garrodian perspective, all genetic variation, including that with only a contributing role in the multifactorial basis of a complex trait and perhaps even some chromosomal (genomic) variation, should be cataloged in OMIM. In the past 20 years, epigenetic variation has become evident as a fourth major etiopathogenetic class, especially in cancer.41,42,43 Chromosomal variations (aberrations) are of interest for MIM/OMIM for several reasons.
FATZ, a filamin-, actinin-, and telethonin-binding protein of the Z-disc of skeletal muscle
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Filamin is an actin-binding protein that is found as different isoforms. Filamin-1 is a non-muscle filamin found in a wide variety of cell types (26), whereas γ-filamin/ABP-L (27) is expressed primarily in heart and skeletal muscle (28, 29). γ-Filamin/ABP-L is also called filamin-2 and has been shown to bind γ- and δ-sarcoglycans, which are members of the dystrophin-glycoprotein complex (30).
We report the identification and characterization of a novel 32-kDa protein expressed in skeletal muscle and located in the Z-disc of the sarcomere. We found that this protein binds to three other Z-disc proteins; therefore, we have named it FATZ, γ-filamin/ABP-L, α-actinin andtelethonin binding protein of the Z-disc. From yeast two-hybrid experiments we are able to show that the SR3-SR4 domains of α-actinin 2 are required to bind the COOH-terminal region of the FATZ as does γ-filamin/ABP-L. Furthermore, by using a glutathione S-transferase overlay assay we find that FATZ also binds telethonin. The level of FATZ protein in muscle cells increases during differentiation, being clearly detectable before the onset of myosin. Although FATZ has no known interaction domains, it would appear to be involved in a complex network of interactions with other Z-band components. On the basis of the information known about its binding partners, we could envisage a central role for FATZ in the myofibrillogenesis. After screening our muscle expressed sequence tag data base and the public expressed sequence tag data bases, we were able to assemble two other muscle transcripts that show a high level of identity with FATZ in two different domains. Therefore, FATZ may be the first member of a small family of novel muscle proteins.
Molecular cloning of human ABPL, an actin-binding protein homologue
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Based on two partial cDNA sequences, a full-length cDNA sequence for an actin-binding like protein previously named ABPL has been isolated and characterized. ABPL is homologous to the human actin-binding proteins ABP-280 and ABP-278. The predicted sequence for ABPL is 2,705 amino acids in length with a calculated molecular mass of 289 kDa. It contains an amino terminal actin-binding domain followed by 24 tandem repeats of approximately 96 amino acids. Two hinge regions, Hinge I and Hinge II, were located prior to repeats 16 and 24, respectively. An isoform of ABPL lacking Hinge I, with a calculated molecular mass of 286 kDa, was also identified by the reverse transcriptase PCR (RT-PCR) method. A comparison with genomic sequences indicated the isoform resulted from alternative RNA splicing. ABPL has a unique insertion sequence of 82 amino acids in repeat 20 that was not present in the other two homologues and has a tissue distribution that was also different from the other two homologues.
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We have cloned and sequenced a 9.4-kilobase cDNA specifying a new 280-kDa protein interacting with the cytoplasmic tail of glycoprotein (Gp) Ibα and showing considerable homology to actin-binding protein 280 (ABP-280) and chicken retinal filamin. We term this protein human β-filamin. The gene for β-filamin localizes to chromosome 3p14.3-p21.1. β-Filamin mRNA expression was observed in many tissues and in cultured human umbilical vein endothelial cells (HUVECs); only minimal expression was detected in platelets and the megakaryocytic cell line CHRF-288. Like ABP-280, β-filamin contains an NH₂-terminal actin-binding domain, a backbone of 24 tandem repeats, and two “hinge” regions. A polyclonal antibody to the unique β-filamin first hinge sequence identifies a strong 280-kDa band in HUVECs but only a weak band in platelets, and stains normal human endothelial cells in culture andin situ. We have confirmed the interaction of β-filamin and GpIbα in platelet and HUVEC lysates. In addition, using two-hybrid analysis with deletion mutants, we have localized the binding domain for GpIbα in β-filamin to residues 1862–2148, an area homologous to the GpIbα binding domain in ABP-280. β-Filamin is a new member of the filamin family that may have significance for GpIbα function in endothelial cells and platelets.
Molecular cloning of tissue-specific transcripts of a transketolase-related gene: Implications for the evolution of new vertebrate genes
1996, Genomics
As part of a systematic search for differentially expressed genes, we have isolated a novel transketolase-related gene (TKR) (HGMW-approved symbol TKT), located between the green color vision pigment gene (GCP) and the ABP-280 filamin gene (FLN1) in Xq28. Transcripts encoding tissue-specific protein isoforms could be isolated. Comparison with known transketolases (TK) demonstrated a TKR-specific deletion mutating one thiamine binding site. Genomic sequencing of the TKR gene revealed the presence of a pseudoexon as well as the acquisition of a tissue-specific spliced exon compared to TK. Since it has been postulated that the vertebrate genome arose by two cycles of tetraploidization from a cephalochordate genome, this could represent an example of the modulation of the function of a preexisting transketolase gene by gene duplication. Thiamine defiency is closely involved with two neurological disorders, Beriberi and Wernicke–Korsakoff syndromes, and in both of these conditions TK with altered activity are found. We discuss the possible involvement of TKR in explaining the observed variant transketolase forms.

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Short CommunicationActin-Binding Protein (ABP-280) Filamin Gene (FLN) Maps Telomeric to the Color Vision Locus (R/GCP) and Centromeric to G6PD in Xq28

Abstract

Short Communication
Actin-Binding Protein (ABP-280) Filamin Gene (FLN) Maps Telomeric to the Color Vision Locus (R/GCP) and Centromeric to G6PD in Xq28