Nemaline body myopathy caused by a novel mutation in troponin T1 (<i>TNNT1</i>)

Abdulhaq, Ulla Najwa; Daana, Muhannad; Dor, Talya; Fellig, Yakov; Eylon, Sharon; Schuelke, Markus; Shaag, Avraham; Elpeleg, Orly; Edvardson, Simon

doi:10.1002/mus.24885

Cited by 41 publications

(64 citation statements)

References 16 publications

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“…This is not unlike the hypothesis put forward for tremor generation in Charcot-Marie-Tooth (CMT) disease, where weight-invariant postural tremors may be present. A search of the literature for mutations in additional sarcomeric proteins associated with myopathy and tremor revealed further cases of patients with mutations in genes encoding thick (MYH2 and MYL2) and thin (TNNT1, TPM3, and NEB) filament proteins (Supplementary Table 2), [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58] suggesting that crossbridge dysregulation may emerge as a myogenic tremor generator beyond the MYBPC1 mutations reported here. Given that our patients do not have a neuropathy and MYBPC1 is expressed purely in skeletal muscle, we hypothesize instead that the tremor is sarcomeric and hence myogenic in origin, but, similar to the denervation tremor, is then picked up by stretch receptors, where it undergoes centrally looped propagation and enhancement, thereby rendering it clinically visible.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…A rearrangement in TNNT1 gene (c.574_577 delins TAGTGCTGT) was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited nemaline myopathy (Abdulhaq, Daana et al 2015). This mutation leads to aberrant splicing that causes a truncation of ssTnT polypeptide at L203.…”

Section: Mutations and Abnormal Expressions Of Tnt Genes In Myopatmentioning

confidence: 99%

TNNT1, TNNT2, and TNNT3: Isoform genes, regulation, and structure–function relationships

Wei

Jin

2016

Gene

176

133

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Troponin T (TnT) is a central player in the calcium regulation of actin thin filament function and is essential for the contraction of striated muscles. Three homologous genes have evolved in vertebrates to encode three muscle type-specific TnT isoforms: TNNT1 for slow skeletal muscle TnT, TNNT2 for cardiac muscle TnT, and TNNT3 for fast skeletal muscle TnT. Alternative splicing and posttranslational modifications confer additional structural and functional variations of TnT during development and muscle adaptation to various physiological and pathological conditions. This review focuses on the TnT isoform genes and their molecular evolution, alternative splicing, developmental regulation, structure-function relationships of TnT proteins, posttranslational modifications, and myopathic mutations and abnormal splicing. The goal is to provide a concise summary of the current knowledge and some perspectives for future research and translational applications.

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“…Patients with distal weakness have also been described, some of whom do not show rods in the muscle biopsies examined . Mutations in TNNT1 encoding troponin T were first identified in the Amish population, but a few patients of Dutch descent and others of non‐Amish origin have also been described . Severe progressive contractures are a feature of these patients, and muscle biopsies can show extensive fibrosis.…”

Section: Nemaline Myopathiesmentioning

confidence: 99%

Myopathology in congenital myopathies

Sewry

Wallgren‐Pettersson

2017

Neuropathology Appl Neurobio

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Congenital myopathies are clinically and genetically a heterogeneous group of early onset neuromuscular disorders, characterized by hypotonia and muscle weakness. Clinical severity and age of onset are variable. Many patients are severely affected at birth while others have a milder, moderately progressive or nonprogressive phenotype. Respiratory weakness is a major clinical aspect that requires regular monitoring. Causative mutations in several genes have been identified that are inherited in a dominant, recessive or X-linked manner, or arise de novo. Muscle biopsies show characteristic pathological features such as nemaline rods/bodies, cores, central nuclei or caps. Small type 1 fibres expressing slow myosin are a common feature and may sometimes be the only abnormality. Small cores (minicores) devoid of mitochondria and areas showing variable myofibrillar disruption occur in several neuromuscular disorders including several forms of congenital myopathy. Muscle biopsies can also show more than one structural defect. There is considerable clinical, pathological and genetic overlap with mutations in one gene resulting in more than one pathological feature, and the same pathological feature being associated with defects in more than one gene. Increasing application of whole exome sequencing is broadening the clinical and pathological spectra in congenital myopathies, but pathology still has a role in clarifying the pathogenicity of gene variants as well as directing molecular analysis.

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Nemaline body myopathy caused by a novel mutation in troponin T1 (TNNT1)

Abstract: This report exemplifies the utility of combining autozygosity mapping and whole exome sequencing and expands the phenotype associated with TNNT1 mutations.

Cited by 41 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

TNNT1, TNNT2, and TNNT3: Isoform genes, regulation, and structure–function relationships

Myopathology in congenital myopathies

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