2. Academic Validation
  3. Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis

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

  • Hum Mutat. 2019 Aug;40(8):1115-1126. doi: 10.1002/humu.23760.
Vandana Shashi 1,  Janelle Geist 2,  Youngha Lee 3,  Yongjin Yoo 3,  Unbeom Shin 4,  Kelly Schoch 1,  Jennifer Sullivan 1,  Nicholas Stong 5,  Edward Smith 6,  Joan Jasien 6,  Peter Kranz 7,  Undiagnosed Diseases Network,  Yoonsung Lee 8,  Yong Beom Shin 9,  Nathan T Wright 10,  Murim Choi 3,  Aikaterini Kontrogianni-Konstantopoulos 2
Affiliations

Affiliations

  • 1 Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, North Carolina.
  • 2 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
  • 3 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 4 School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
  • 5 Institute for Genomic Medicine, Columbia University, New York, New York.
  • 6 Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, North Carolina.
  • 7 Division of Neuroradiology, Department of Radiology, Duke Health, Durham, North Carolina.
  • 8 Center for Genomic Integrity, Institute for Basic Science, Ulsan, Republic of Korea.
  • 9 Department of Rehabilitation Medicine, Pusan National University College of Medicine, Pusan, Republic of Korea.
  • 10 Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, Virginia.
PMID: 31264822 DOI: 10.1002/humu.23760
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.

Keywords

MYBPC1; arthrogryposis; hypotonia; myopathy; myosin binding protein-C; tremor.

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