Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis

Abstract

Encoding the slow skeletal muscle isoform of myosin binding protein‐C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M‐motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M‐motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M‐motif to myosin, which likely impairs the formation of actomyosin cross‐bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early‐onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.

Making waves: A proposed new role for myosin-binding protein C in regulating oscillatory contractions in vertebrate striated muscle

“…Conversely, dysregulation of SPOCs may cause or exacerbate the clinical course of diseases involving MyBP-C, because MyBP-C protein expression and phosphorylation are commonly reduced in cardiac diseases (van Dijk et al, 2009;Glazier et al, 2019;Kraft et al, 2016). Inherited mutations in the slow skeletal isoform of MyBP-C (MYBPC1) are also increasingly linked to distal arthrogryposes and muscle tremor (Shashi et al, 2019; Journal of General Physiology 10 of 15 Making waves with MyBP-C https://doi.org/10.1085/jgp.202012729 Stavusis et al, 2019). In the case of cardiac muscle, mutations in MYBPC3 are among the most frequent causes of HCM, where most mutations lead to reduced cMyBP-C protein expression (haploinsufficiency; Yotti et al, 2019;Helms et al, 2014).…”

Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor

“…Dominant missense and recessive nonsense pathogenic variants in MYBPC1 located in the NH 2 and COOH termini were previously associated with the development of severe and lethal forms of distal arthrogryposis (DA) (5)(6)(7)(8)(9)(10). Recently, dominant missense pathogenic variants residing within the NH 2 -terminal M-motif of sMyBP-C have been causatively linked to a new form of early-onset myopathy characterized by hypotonia, muscle weakness, dysmorphia, skeletal deformities, and a posturally pronounced, high-frequency tremor, likely of myogenic origin (11,12).…”

IGF1 haploinsufficiency in children with short stature: a case series

“…Finally, the MYBPC1 gene is also deleted in all patients except patient 4. Missense mutations in this gene were described in association with autosomal dominant distal arthrogryposis type 1B and with congenital myopathy with tremor (26,27,28). The absence of distal contractures and congenital hypotonia in our patients is an argument to attribute a dominant negative effect to the reported MYBPC1 missense mutations rather than a pathological mechanism based on haploinsufficiency.…”