A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy

• Published in: PloS one 2017-10, Vol.12 (10), p.e0186642-e0186642
• Main Authors: Rossi, Daniela, Palmio, Johanna, Evilä, Anni, Galli, Lucia, Barone, Virginia, Caldwell, Tracy A, Policke, Rachel A, Aldkheil, Esraa, Berndsen, Christopher E, Wright, Nathan T, Malfatti, Edoardo, Brochier, Guy, Pierantozzi, Enrico, Jordanova, Albena, Guergueltcheva, Velina, Romero, Norma Beatriz, Hackman, Peter, Eymard, Bruno, Udd, Bjarne, Sorrentino, Vincenzo
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Adult; BASIC BIOLOGICAL SCIENCES; Biochemistry; Biopsy; Bulgarian people; Chemistry; Comparative analysis; Connectin; crystal structure; desmin; Disks; Distal Myopathies - diagnostic imaging; Distal Myopathies - genetics; Distal Myopathies - pathology; Dystrophy; Female; Filamins - genetics; Frameshift Mutation; Gene mutation; Genes; Genetic aspects; Genetic Carrier Screening; Genetic variation; hands; Hospitals; Human health and pathology; Humans; Life Sciences; Magnetic Resonance Imaging; Male; Medicine; Middle Aged; Morphology; muscular dystrophies; Muscular dystrophy; Mutation; Myopathy; Neuromuscular diseases; NMR; Nuclear magnetic resonance; Patients; Pedigree; Physiological aspects; Proteins; Rho Guanine Nucleotide Exchange Factors - genetics; Risk factors; skeletal muscles; structural proteins; Structure-function relationships; Whole Exome Sequencing
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0186642

A novel FLNC c.5161delG (p.Gly1722ValfsTer61) mutation was identified in two members of a French family affected by distal myopathy and in one healthy relative. This FLNC c.5161delG mutation is one nucleotide away from a previously reported FLNC mutation (c.5160delC) that was identified in patients and in asymptomatic carriers of three Bulgarian families with distal muscular dystrophy, indicating a low penetrance of the FLNC frameshift mutations. Given these similarities, we believe that the two FLNC mutations alone can be causative of distal myopathy without full penetrance. Moreover, comparative analysis of the clinical manifestations indicates that patients of the French family show an earlier onset and a complete segregation of the disease. As a possible explanation of this, the two French patients also carry a OBSCN c.13330C>T (p.Arg4444Trp) mutation. The p.Arg4444Trp variant is localized within the OBSCN Ig59 domain that, together with Ig58, binds to the ZIg9/ZIg10 domains of titin at Z-disks. Structural and functional studies indicate that this OBSCN p.Arg4444Trp mutation decreases titin binding by ~15-fold. 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 in the French family.