A novel in‐frame deletion in MYOT causes an early adult onset distal myopathy

Abstract

Missense mutations in MYOT encoding the sarcomeric Z‐disk protein myotilin cause three main myopathic phenotypes including proximal limb‐girdle muscular dystrophy, spheroid body myopathy, and late‐onset distal myopathy. We describe a family carrying a heterozygous MYOT deletion (Tyr4_His9del) that clinically was characterized by an early‐adult onset distal muscle weakness and pathologically by a myofibrillar myopathy (MFM). Molecular modeling of the full‐length myotilin protein revealed that the 4‐YERPKH‐9 amino acids are involved in local interactions within the N‐terminal portion of myotilin. Injection of in vitro synthetized mutated human MYOT RNA or of plasmid carrying its cDNA sequence in zebrafish embryos led to muscle defects characterized by sarcomeric disorganization of muscle fibers and widening of the I‐band, and severe motor impairments. We identify MYOT novel Tyr4_His9 deletion as the cause of an early‐onset MFM with a distal myopathy phenotype and provide data supporting the importance of the amino acid sequence for the structural role of myotilin in the sarcomeric organization of myofibers.

Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in Amyotrophic Lateral Sclerosis

“…Future experiments are needed to better characterize this protein and the functional implications of arginine dimethylation on skeletal muscle atrophy. However, mutations in MYOT have previously been associated with myopathy 69 .…”

A case report of adolescent myofibrillar myopathy due to a de novo R406W pathogenic variant in desmin with symptoms of “hypertrophic cardiomyopathy”

“…MFM is transmitted in an autosomal dominant manner, but a few MFMs are also inherited through autosomal recessive inheritance [ 2 ]. Gene implicated in MFM includes DES [ 3 ], α-B-crystallin ( CRYAB ) [ 4 ], myotilin ( MYOT ) [ 5 ], Filamin C ( FLNC ) [ 6 ], Bcl-2-associated athanogene 3 [ 7 ], Four-and-a-half LIM protein-1 [ 8 ], Plectin [ 9 ], Titin [ 10 ] etc. Of these, MFM caused by abnormal accumulation of Desmin protein, known as desminopathy, is the most common form of MFM.…”