A novel MYH7 Leu1453pro mutation resulting in Laing distal myopathy in an Irish family

Lefter, Stela; Hardiman, Orla; McLaughlin, Russell L.; Murphy, Sinéad M.; Farrell, Michael; Ryan, Aisling

doi:10.1016/j.nmd.2014.09.007

Cited by 9 publications

(7 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and D.H., unpublished observations). 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), suggesting that cross‐bridge dysregulation may emerge as a myogenic tremor generator beyond the MYBPC1 mutations reported here. Additional studies in transgenic animals to further elucidate the physiology of this novel type of tremor and get more insight into tremor‐causing mechanisms are in preparation.…”

Section: Discussionmentioning

confidence: 84%

“…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%

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

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 84%

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

View full text Add to dashboard Cite

show abstract

“…Patients with distal myopathy due to MYH7 mutations may develop dCMP. 103) 104) An uncommon but important manifestation of CI in distal myopathy due to MYH7 mutations is LVHT. 105) X-linked distal myopathy due to FHL1 mutations may accompany hCMP.…”

Section: Resultsmentioning

confidence: 99%

Heart Disease in Disorders of Muscle, Neuromuscular Transmission, and the Nerves

Finsterer

Stöllberger

2016

Korean Circ J

View full text Add to dashboard Cite

Little is known regarding cardiac involvement (CI) by neuromuscular disorders (NMDs). The purpose of this review is to summarise and discuss the major findings concerning the types, frequency, and severity of cardiac disorders in NMDs as well as their diagnosis, treatment, and overall outcome. CI in NMDs is characterized by pathologic involvement of the myocardium or cardiac conduction system. Less commonly, additional critical anatomic structures, such as the valves, coronary arteries, endocardium, pericardium, and even the aortic root may be involved. Involvement of the myocardium manifests most frequently as hypertrophic or dilated cardiomyopathy and less frequently as restrictive cardiomyopathy, non-compaction, arrhythmogenic right-ventricular dysplasia, or Takotsubo-syndrome. Cardiac conduction defects and supraventricular and ventricular arrhythmias are common cardiac manifestations of NMDs. Arrhythmias may evolve into life-threatening ventricular tachycardias, asystole, or even sudden cardiac death. CI is common and carries great prognostic significance on the outcome of dystrophinopathies, laminopathies, desminopathies, nemaline myopathy, myotonias, metabolic myopathies, Danon disease, and Barth-syndrome. The diagnosis and treatment of CI in NMDs follows established guidelines for the management of cardiac disease, but cardiotoxic medications should be avoided. CI in NMDs is relatively common and requires complete work-up following the establishment of a neurological diagnosis. Appropriate cardiac treatment significantly improves the overall long-term outcome of NMDs.

show abstract

“…There have been only a few families encountered worldwide with genetically proven Laing myopathy (1, 2,3,4,6,7,9,10,11,12,13,14,16). Here, we describe a four-generation family with four affected members in 2 generations with Laing myopathy and additional features with a mutation in exon 34 of the MYH7 gene that has not as been reported so far.…”

Section: Introductionmentioning

confidence: 84%

“…All of these mutations are localized in the rod domain of the protein . Cases have been described from Australia, Central Europe, and USA(2,3,4, 6,7,10,11,12,13,14,15). Only while the present paper was under consideration already, a larger cohort of 21 families with 12 novel mutations originating from several countries and three continents has been published(9).…”

mentioning

confidence: 93%