Genetic Abnormalities in a Calf with Congenital Increased Muscular Tonus

Wiedemar, Natalie; Riedi, Anna-Katharina; Jagannathan, Vidhya; Drögemüller, Cord; Meylan, Mireille

doi:10.1111/jvim.13599

Cited by 11 publications

(16 citation statements)

References 16 publications

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“…40 Notably, a de-novo mutation in MYBPC1, c.885T>G p.Leu295Arg, has been identified in a calf with weakness, stiffness, and muscle tremor. 41 The c.885T>G p.Leu295Arg mutation also resides in the M-motif of bovine MYBPC1 and corresponds to amino acid p.Leu263Arg in exon 11 of the human gene, the same exon affected in our families.…”

Section: Discussionmentioning

confidence: 71%

“…41 Detailed clinical tremor analysis, including physiological studies, in two patients from family 2 argued against both physiological and enhanced physiological tremor generated by mechanical reflex oscillations, although up to 10% of controls and of individuals with enhanced physiological tremor may show a weight-invariant tremor frequency. 41 Detailed clinical tremor analysis, including physiological studies, in two patients from family 2 argued against both physiological and enhanced physiological tremor generated by mechanical reflex oscillations, although up to 10% of controls and of individuals with enhanced physiological tremor may show a weight-invariant tremor frequency.…”

Section: Discussionmentioning

confidence: 99%

“…The most distinctive aspect of this new phenotype associated with specific MYBPC1 mutations is the obligatory tremor in all mutation carriers, which also appeared to be a prominent feature of the spontaneous animal model of the disease. 41 Detailed clinical tremor analysis, including physiological studies, in two patients from family 2 argued against both physiological and enhanced physiological tremor generated by mechanical reflex oscillations, although up to 10% of controls and of individuals with enhanced physiological tremor may show a weight-invariant tremor frequency. The lack of tremor frequency change after weight loading would typically be considered to be compatible with a central pacemaker at the origin of the tremor.…”

Section: Discussionmentioning

confidence: 99%

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

Stavusis

Lāce

Schäfer³

et al. 2019

Annals of Neurology

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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 NH 2 -terminal M-motif of sMyBP-C. Both mutations result in markedly increased binding of the NH 2 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."Circular dichroism experiments were conducted in a 1-mm pathlength cuvette with wild-type and mutant His-tagged proteins of 15 to 17μM in 20mM phosphate buffer (pH 7.5) and 50mM NaCl. Samples were measured in triplicate at temperatures from 20 C to 90 C in 10 C intervals on a Jasco J-810 spectrophotometer. 132 Volume 86, No. 1

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Stavusis

Lāce

Schäfer³

et al. 2019

Annals of Neurology

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show abstract

“…This same variant was later associated with increased muscle size in the same breed, and increased MYBPC1 gene expression was also associated with steers developing more muscle mass [99], potentially implicating ssMyBP-C in muscle growth. Additionally, a de novo mutation was identified in a female calf presenting with a DA1-like phenotype [100]. This mutation caused a point mutation, L295R, within the M-domain, which was not present in either parent.…”

Section: Introductionmentioning

confidence: 99%

Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology

McNamara

Sadayappan

2018

Archives of Biochemistry and Biophysics

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The Myosin Binding Protein-C (MyBP-C) family is a group of sarcomeric proteins important for striated muscle structure and function. Comprising approximately 2% of the myofilament mass, MyBP-C has important roles in both contraction and relaxation. Three paralogs of MyBP-C are encoded by separate genes with distinct expression profiles in striated muscle. In mammals, cardiac MyBP-C is limited to the heart, and it is the most extensively studied owing to its involvement in cardiomyopathies. However, the roles of two skeletal paralogs, slow and fast, in muscle biology remain poorly characterized. Nonetheless, both have been recently implicated in the development of skeletal myopathies. This calls for a better understanding of their function in the pathophysiology of distal arthrogryposis. This review characterizes MyBP-C as a whole and points out knowledge gaps that still remain with respect to skeletal MyBP-C.

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“…Moreover, two recessive variants, p.Arg318* and p.Glu186Lys, have been connected to lethal congenital contracture syndrome 4 (LCCS4: MIM# 614915) and an Arthrogryposis Multiplex Congenita presentation, respectively (Ekhilevitch et al, ; Markus et al, ). Lastly, a calf containing the de novo p.Leu295Arg variant was described to have congenital muscle tremor, weakness, contractures, and inability to fully extend its limbs, with the subsequent spontaneous improvement of motor strength (Wiedemar, Riedi, Jagannathan, Drogemuller, & Meylan, ). Interestingly, five of the six human MYBPC1 variants and the calf variant are located in the NH 2 ‐terminus of the molecule suggesting that it may be a hot spot for deleterious variants (Figure a).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Genetic Abnormalities in a Calf with Congenital Increased Muscular Tonus

Cited by 11 publications

References 16 publications

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

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

Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology

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

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