A Novel FLNC Frameshift and an OBSCN Variant in a Family with Distal Muscular Distrophy

Abstract

Distal muscular dystrophies are a group of inherited primary muscle disorders showing progressive muscle atrophy and weakness preferentially in the hands and/or feet. We identified a novel frameshift mutation in the filamin C (FLNC c.5161delG) gene in two members of a French family affected by distal myopathy and in one healthy relative. Interestingly, the two affected members, but not the healthy relative, also carry a p.Arg4444Trpvariant in the gene coding for the giant protein obscurin(OBSCN). Both OBSCN and FLNC are Z-disk associated proteins. FLNC is an actin cross-linking protein, involved with Z-disk organization and muscle integrity. The FLNC c.5161delG mutation here described is one nucleotide away from a previously reported FLNC mutation (c.5160delC), identified in patients and in asymptomatic carriers of three families with distal muscular dystrophy, indicating a low penetrance of these FLNC frameshift mutations. Obscurin is a giant protein, which interacts with titin at both the M-band and the Z-disk and with muscle-specific ankyrins at the sarcoplasmic reticulum and the sarcolemma. The p.Arg4444Trpvariant we identified is localized within the OBSCN Ig59 that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicated that the OBSCN p.Arg4444Trp variant results in a 10-fold decrease in binding to titin. Interestingly, in vitro and in vivo models show that loss of FLNC results in myofibril destabilization and that the decrease in the interaction between titin and obscurin is associated with cardiac and skeletal muscle diseases. On this line, we suggest that the combination of the OBSCN p.Arg4444Trp variant and of the FLNC c.5161delG mutation can cooperatively affect myofibril stability and increase the penetrance of muscular dystrophy.