Exome sequencing identifies variants in two genes encoding the lim-proteins n-rap and fhl1 in a bag3 myofibrillar myopathy

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. The c.626 C>T (P209L) mutation in BAG3 gene has been described as causative of MFM. In this work, we aimed to further investigate the genetic basis of BAG3 MFM with whole exome sequencing (WES). A MFM female patient carrying the c.626 C>T (P209L) mutation in BAG3 gene and her unaffected parents and brother were studied with WES. Quantitative Real Time PCR, immunohistochemistry and Western Blot analysis were performed to describe mRNA and protein pattern of expression of the identified genes. Besides the known mutation in BAG3, the patient carried variants in N-RAP and FHL1 genes that encode muscle specific LIM domain containing proteins. These variants are associated with a decreased expression of NRAP and accumulation of FHL1 in aggregates in the patient\u2019s skeletal muscle tissue. Molecular dynamic analysis of the mutated FHL1 domain suggests a modification of its surface charge, which could explain FHL1 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