2. Academic Validation
  3. Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy

Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy

  • Ann Neurol. 2019 Jul;86(1):129-142. doi: 10.1002/ana.25494.
Janis Stavusis 1,  Baiba Lace 1 2,  Jochen Schäfer 3,  Janelle Geist 4,  Inna Inashkina 1,  Dita Kidere 1,  Sander Pajusalu 5 6,  Nathan T Wright 7,  Annika Saak 3,  Manja Weinhold 3,  Dietrich Haubenberger 8,  Sandra Jackson 3,  Aikaterini Kontrogianni-Konstantopoulos 4,  Carsten G Bönnemann 9
Affiliations

Affiliations

  • 1 Latvian Biomedical Research and Study Centre, Riga, Latvia.
  • 2 Centre Hospitalier Universitaire de Québec, Ville de Québec, QC, Canada.
  • 3 Department of Neurology-Uniklinikum CG Carus, Dresden, Germany.
  • 4 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD.
  • 5 Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
  • 6 Department of Clinical Genetics, Institute of Clinical Medicine, Tartu University, Tartu, Estonia.
  • 7 Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, VA.
  • 8 Clinical Trials Unit, Office of the Clinical Director, NINDS Intramural Research Program, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
  • 9 Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
PMID: 31025394 DOI: 10.1002/ana.25494
Abstract

Objective: To define a distinct, dominantly inherited, mild skeletal myopathy associated with prominent and consistent tremor in two unrelated, three-generation families.

Methods: Clinical evaluations as well as exome and panel Sequencing analyses were performed in affected and nonaffected members of two families to identify genetic variants segregating with the phenotype. Histological assessment of a muscle biopsy specimen was performed in 1 patient, and quantitative tremor analysis was carried out in 2 patients. Molecular modeling studies and biochemical assays were performed for both mutations.

Results: Two novel missense mutations in MYBPC1 (p.E248K in family 1 and p.Y247H in family 2) were identified and shown to segregate perfectly with the myopathy/tremor phenotype in the respective families. MYBPC1 encodes slow Myosin binding protein-C (sMyBP-C), a modular sarcomeric protein playing structural and regulatory roles through its dynamic interaction with actin and Myosin filaments. The Y247H and E248K mutations are located in the NH2 -terminal M-motif of sMyBP-C. Both mutations result in markedly increased binding of the NH2 terminus to Myosin, possibly interfering with normal cross-bridge cycling as the first muscle-based step in tremor genesis. The clinical tremor features observed in all mutation carriers, together with the tremor physiology studies performed in family 2, suggest amplification by an additional central loop modulating the clinical tremor phenomenology.

Interpretation: Here, we link two novel missense mutations in MYBPC1 with a dominant, mild skeletal myopathy invariably associated with a distinctive tremor. The molecular, genetic, and clinical studies are consistent with a unique sarcomeric origin of the tremor, which we classify as "myogenic tremor." ANN NEUROL 2019.

Figures