MYBPC1 mutations in distal arthrogryposis and congenital tremor

The sarcomere is the fundamental contractile unit of striated muscle, and its precise structural organization is essential for coordinated muscle contraction and relaxation. The development of various skeletal muscle myopathies has been linked to dysregulation of the contractile machinery within the sarcomere. Myosin binding protein-C (MyBP-C) is a key sarcomeric regulator that modulates thick filament stability and actomyosin cross-bridge dynamics. Among its paralogs, slow skeletal MyBP-C (sMyBP-C), encoded by MYBPC1, has emerged as a critical determinant of skeletal muscle function. Recent genetic and mechanistic studies have linked MYBPC1 mutations to a spectrum of congenital muscle disorders, including distal arthrogryposis (DA) and congenital myopathy with tremor (MYOTREM). DA is characterized by congenital joint contractures primarily affecting distal limbs and is strongly associated with fetal akinesia resulting from impaired muscle contractility. In contrast, MYOTREM represents a distinct myogenic tremor disorder caused by altered sarcomere function, leading to dysregulated cross-bridge cycling and oscillatory force generation. Advances in genetic sequencing have led to the identification of multiple pathogenic MYBPC1 variants, particularly within the N-terminal M-motif, highlighting this region as a functional hotspot. This review integrates current knowledge on the molecular, genetic, and clinical features of MYBPC1-associated disorders, emphasizing a unifying model in which disease phenotypes exist along a continuum of sarcomeric dysfunction in a mutation-specific manner, ranging from mild to lethal depending on the location of the mutation within the MyBP-C functional regions. Despite increasing mechanistic insight, current treatments remain largely focused on symptom management. Future studies combining human genetics, animal models, and functional analyses are essential to advance targeted therapeutic strategies.