Mutations in the N-terminal Actin-Binding Domain of Filamin C Cause a Distal Myopathy

• Published in: American journal of human genetics Vol. 88; no. 6; pp. 729 - 740
• Main Authors: DUFF, Rachael M, TAY, Valerie, SONG, Jaeguen, DJINOVIC-CARUGO, Kristina, PENTTILÄ, Sini, RAHEEM, Olayinka, REARDON, Katrina, MALANDRINI, Alessandro, GAMBELLI, Simona, VILLANOVA, Marcello, NOWAK, Kristen J, WILLIAMS, David R, HACKMAN, Peter, LANDERS, John E, BROWN, Robert H, UDD, Bjarne, LAING, Nigel G, RAVENSCROFT, Gianina, MCLEAN, Catriona, KENNEDY, Paul, STEINBACH, Alina, SCHÖFFLER, Wiebke, VAN DER VEN, Peter F. M, FÜRST, Dieter O
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Cell Press 10.06.2011; Elsevier
• Subjects: Actins - metabolism; Adult; Aged; Australia; Biological and medical sciences; Chromosomes; Chromosomes, Human, Pair 7 - genetics; Contractile Proteins - genetics; Contractile Proteins - metabolism; Distal Myopathies - genetics; Distal Myopathies - metabolism; Distal Myopathies - pathology; Female; Filamins; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Humans; Italy; Male; Medical genetics; Medical sciences; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Middle Aged; Molecular and cellular biology; Musculoskeletal diseases; Mutation; Pedigree; Protein Structure, Tertiary - genetics; Proteins; Australia; Italy; Human; Actin; Distal; Genetics; Mutation; Terminal; Myopathy
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.04.021

Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.