| *102565 | ||||||||||||||||||||||||||||||||||||
| FILAMIN C; FLNC | ||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||
| FILAMIN, GAMMA FILAMIN 2; FLN2 ACTIN-BINDING PROTEIN 280, AUTOSOMAL FORM; ABP280A ABPA ACTIN-BINDING PROTEIN-LIKE; ABPL | ||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: FLNC | ||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 7q32.1 Genomic coordinates (GRCh37): 7:128,470,482 - 128,499,327 (from NCBI) | ||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||
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| TEXT | ||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||
| Filamins, such as FLNC, are a family of actin (see ACTA1; 102610)-binding proteins involved in reshaping of the cytoskeleton. See FLN1 (FLNA; 300017) for background information on the filamin gene family. | ||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||
| Xie et al. (1998) cloned FLNC, which they called ABPL, from a heart cDNA library. The deduced 2,705-amino acid protein has a calculated molecular mass of 289 kD. ABPL contains an N-terminal actin-binding domain, followed by 24 repeats of about 94 amino acids. It has hinge sequences prior to repeats 16 and 24. Xie et al. (1998) also identified an alternatively spliced transcript that encodes a protein lacking hinge 1. PCR analysis detected transcripts encoding the hinge 1-containing isoform in stomach, uterus, umbilical vein endothelial cells, and prostate. Transcripts encoding both isoforms were detected in heart, thyroid, fetal brain, fetal lung, retina, spinal cord, skeletal muscle, and bone marrow. Using sarcoglycan-gamma (SGCG; 608896) as bait in a yeast 2-hybrid screen of a skeletal muscle cDNA library, followed by EST database analysis and screening of a skeletal muscle cDNA library, Thompson et al. (2000) cloned FLNC, which they called FLN2. The deduced 2,688-amino acid protein shares 74% and 71% identity with FLN1 and filamin-beta (FLNB; 603381), respectively, and the 3 proteins are nearly 100% identical in the actin-binding domains. FLN2 lacks the first hinge region present in FLN1 and FLNB, but it has the second hinge region. Like FLN1 and FLNB, FLNC has a C-terminal domain containing binding sites for several receptor proteins. Western blot analysis detected a 280-kD protein in heart and skeletal muscle. | ||||||||||||||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||||||||||||||
| By yeast 2-hybrid analysis, Thompson et al. (2000) found that sarcoglycan-gamma and -delta (SGCD; 601411) interacted with FLN2, but sarcoglycan-alpha (SGCA; 600119) and -beta (SGCB; 600900) did not. In vitro binding assays indicated that FLN2 interacted directly with sarcoglycan-gamma and -delta, but not with dystrophin (DMD; 300377) and syntrophin beta-1 (SNTB1; 600026). Coimmunoprecipitation analysis of transfected proteins and of endogenous proteins in mouse myotube lysates confirmed that FLN2 interacted with sarcoglycans-gamma and -delta. Fln2 was detected predominantly in the soluble fraction of lysed mouse myotube cultures. Immunoelectron microscopy detected 2 pools of Fln2, one adjacent to the sarcolemmal membrane and the other more diffuse. Thompson et al. (2000) found elevated levels of membrane-associated FLN2 in 2 patients with limb-girdle muscular dystrophy type 2C (LGMD2C; 253700), a patient with Duchenne muscular dystrophy (DMD; 310200), and dystrophic mice. The KY protein (605739) has been implicated in a neuromuscular dystrophy in the mouse, but its role in muscle function remains unclear. Beatham et al. (2004) showed that KY interacted with several sarcomeric cytoskeletal proteins including filamin C and the slow isoform of the myosin-binding protein C (MYBPC1; 160794). A role for KY in regulating filamin C function in vivo was supported by the expression analysis of filamin C in the Ky-null mouse mutant, where distinct irregular subcellular localization of filamin C was found in subsets of muscle fibers, which appeared to be a specific outcome of KY deficiency. In vitro assays showed that KY has protease activity, and specific degradation of filamin C by KY was shown in transfected cells. Beatham et al. (2004) suggested that KY may be an intrinsic part of the protein networks underlying the molecular mechanism of several limb-girdle muscular dystrophies, particularly those where interactions between filamin C and disease-causing proteins have been shown. | ||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||
| Gariboldi et al. (1994) mapped the FLN2 gene to human chromosome 7q32-q35 by analysis of somatic cell hybrids containing portions of chromosome 7. Chakarova et al. (2000) assigned the FLNC gene to 7q32 by radiation hybrid analysis. By interspecific backcross analysis, Gariboldi et al. (1994) mapped the mouse homolog to chromosome 6 in a region showing homology of synteny to human chromosome 7. Pseudogene An FLNC pseudogene maps to chromosome 7q32-q35 about 53.7 kb downstream from the functional FLNC gene. The pseudogene is 98% homologous to exons 46, 47, and 48 of the functional gene (van der Ven et al., 2010). | ||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||
| In affected members of a German family with autosomal dominant filamin C-related myofibrillar myopathy (609524), Vorgerd et al. (2005) identified a heterozygous mutation in the FLNC gene (102565.0001). In a German mother and daughter with adult-onset limb-girdle muscle weakness, Shatunov et al. (2009) identified a heterozygous deletion in the FLNC gene (102565.0002). This family was the only 1 of 127 families with a myopathy examined that was found to have an FLNC mutation, indicating that this subtype of myofibrillar myopathy is very rare. Kono et al. (2010) identified a heterozygous 1-bp deletion (8107delG) in exon 48 of the FLNC gene in affected members of a Japanese family with adult-onset myofibrillar myopathy primarily affecting the distal limbs, with later involvement of proximal muscles. However, the paper was later retracted by the authors after the mutation was found to occur in the FLNC pseudogene, based on the report of van der Ven et al. (2010). Van der Ven et al. (2010) noted that the pseudogene is 98% homologous to exons 46, 47, and 48 of the functional FLNC gene and that the pseudogene contains the 8107delG variant. By linkage analysis followed by candidate gene sequencing of an Australian family with distal myopathy-4 (MPD4; 614065), reported by Williams et al. (2005), Duff et al. (2011) identified a heterozygous mutation in the FLNC gene (M251T; 102565.0003). A different heterozygous mutation (A193T; 102565.0004) was found in affected members of an Italian family with the same phenotype. Both mutations occurred in the actin-binding domain, and in vitro cellular expression studies showed that both mutations resulted in increased affinity for actin. | ||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||
| .0001 MYOPATHY, MYOFIBRILLAR, FILAMIN C-RELATED | ||||||||||||||||||||||||||||||||||||
| FLNC, TRP2710TER [dbSNP:rs121909518] | ||||||||||||||||||||||||||||||||||||
| In affected members of a German family with autosomal dominant filamin C-related myofibrillar myopathy (609524), Vorgerd et al. (2005) identified a heterozygous 8130G-A transition in exon 48 of the FLNC gene, resulting in a trp2710-to-ter (W2710X) substitution. The mutation leads to a truncation of the filamin C immunoglobulin domain that is responsible for dimerization. Functional expression studies showed that the W2710X protein had improper folding, was unable to form dimers, and showed abnormal aggregation. The findings implied that dimer formation is essential for the biologic function of filamin. The mutation was not identified in 220 control chromosomes. By in vitro functional expression studies, Lowe et al. (2007) showed that W2710X-mutant protein was less stable and more susceptible to proteolysis compared to wildtype. The mutant protein did not dimerize properly and formed filamin aggregates in cultured cells. Aggregation of mutant protein did not affect dimerization of wildtype filamin C, and the mutant protein still showed normal binding to actin and sarcoglycans. | ||||||||||||||||||||||||||||||||||||
| .0002 MYOPATHY, MYOFIBRILLAR, FILAMIN C-RELATED | ||||||||||||||||||||||||||||||||||||
| FLNC, 12-BP DEL, NT2997 | ||||||||||||||||||||||||||||||||||||
| In a German mother and daughter with autosomal dominant filamin C-related myofibrillar myopathy (609524), Shatunov et al. (2009) identified a heterozygous 12-bp deletion (2997_3008del) in exon 18 of the FLNC gene, predicted to result in an in-frame deletion of 4 residues (val930 to thr933) in the seventh repeat and confirmed by RT-PCR analysis of muscle tissue from the affected daughter. The phenotype was characterized by adult-onset muscle weakness initially involving proximal muscles of the lower limbs and spreading to the upper limbs and distal muscles of lower extremities. Both had paraspinal and abdominal muscle involvement and winging of the scapula. Cardiac and respiratory muscles were not affected. Skeletal muscle biopsy from the daughter showed marked variation in fiber size, some fibers with internal nuclei, and type 1 fiber predominance. Several fibers showed polymorphous hyaline and nonhyaline myofibrillary FLNC-positive inclusions with a convoluted, serpentine appearance. Ultrastructural examination showed major myofibrillar abnormalities, with accumulation of Z disc debris, granulofilamentous material, and nemaline rods. There were also mitochondrial aggregates. | ||||||||||||||||||||||||||||||||||||
| .0003 MYOPATHY, DISTAL, 4 | ||||||||||||||||||||||||||||||||||||
| FLNC, MET251THR | ||||||||||||||||||||||||||||||||||||
| In affected members of a large Australian family with autosomal dominant distal myopathy-4 (MPD4; 614065) originally reported by Williams et al. (2005), Duff et al. (2011) identified a heterozygous 752T-C transition in exon 4 of the FLNC gene, resulting in a met251-to-thr (M251T) substitution in a highly conserved residue in the CH2 domain in the actin-binding domain. The mutation was not found in 400 control chromosomes. The mutant protein had slightly decreased thermal stability and showed increased actin-binding activity compared to the wildtype protein. Transfection of the mutant M251T protein into cells showed significantly decreased nuclear localization compared to wildtype and resulted in the formation of intracellular protein aggregates. Duff et al. (2011) concluded that the disease mechanism somehow involves increased affinity for actin. The phenotype was characterized by adult onset of distal muscle weakness and atrophy affecting the upper and lower limbs, with nonspecific findings on muscle biopsy. | ||||||||||||||||||||||||||||||||||||
| .0004 MYOPATHY, DISTAL, 4 | ||||||||||||||||||||||||||||||||||||
| FLNC, ALA193THR | ||||||||||||||||||||||||||||||||||||
| In affected members of an Italian family with autosomal dominant distal myopathy-4 (MPD4; 614065), Duff et al. (2011) identified a heterozygous 577G-A transition in exon 2 of the FLNC gene, resulting in an ala193-to-thr (A193T) substitution in a highly conserved residue in the CH2 domain in the actin-binding domain. The mutation was not found in 204 control chromosomes. The mutant protein had slightly decreased thermal stability and showed increased actin-binding activity compared to the wildtype protein. Nuclear localization was unaltered, but transfection resulted in the formation of intracellular protein aggregates. Duff et al. (2011) concluded that the disease mechanism somehow involves increased affinity for actin. The phenotype was characterized by adult onset of distal muscle weakness and atrophy affecting the upper and lower limbs, with nonspecific findings on muscle biopsy. | ||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||
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