Myofibrillar myopathies (MFMs) are genetically heterogeneous dystrophies characterized by disintegration of Z-disks and myofibrils. The characteristic degradation of myofibrils is followed by ectopic accumulation of multiple proteins. MFMs have been associated with mutations in genes encoding Z-disk or Z-disk-related proteins. Recently, BAG3 mutation has been described as causative of MFM. At now, the genetic basis of MFM with BAG 3 mutation is not fully traced. In this work we studied by exome sequencing a MFM female patient carrying the c.626 C>T (P209L) mutation in BAG3 gene. We found that this BAG3 variant is associated to mutations of N-RAP and FHL1 genes that encode muscle specific LIM domain containing proteins resulting in a decreased expression of NRAP and FLH1 accumulation in aggregates in affected skeletal muscle tissue. Molecular dynamic analysis of mutated FHL1 domain suggests a modification of its surface charge, which could explain its accumulation in muscle fibers. To our knowledge this is the first study reporting the simultaneous presence of genetic variants in three genes possibly causative of MFM: BAG3 and FHL1, already independently associated to MFMs, and NRAP linked for the first time to MFM.
|Titolo:||Exome sequencing identifies mutations in two genes encoding the LIM-proteins N-RAP and FHL1 in a BAG3 myofibrillar myopathy|
|Data di pubblicazione:||18-mag-2015|
|Settore Scientifico Disciplinare:||Settore MED/26 - Neurologia|
|Citazione:||Exome sequencing identifies mutations in two genes encoding the LIM-proteins N-RAP and FHL1 in a BAG3 myofibrillar myopathy / M. Meregalli, F. C. D’Avila, S. Lupoli, M. Barcella, A. Orro, F. De Santis, C.Sitzia, A. Farini, P. D’Ursi, S.Erratico, L. Milanesi, D. Braga, D. Cusi, C. Barlassina, Y.Torrente. ((Intervento presentato al 12. convegno Congress of Mediterranean Society of Miology tenutosi a Napoli nel 2015.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|