scholarly journals Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

2020 ◽  
pp. jmedgenet-2019-106714
Author(s):  
Justine Géraud ◽  
Klaus Dieterich ◽  
John Rendu ◽  
Emmanuelle Uro Coste ◽  
Murielle Dobrzynski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nonsense Mutation ◽  
Clinical Phenotype ◽  
Troponin T ◽  
Early Death ◽  
Nemaline Myopathy ◽  
Homozygous Deletion ◽  
Muscle Fibres ◽  
Muscle Fibre Size ◽  
Pathogenic Variants

BackgroundCongenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres.MethodsUsing next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform.ResultsThe clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations.DiscussionThe clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.

scholarly journals Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy

2019 ◽  
Author(s):  
Jacob A Ross ◽  
Yotam Levy ◽  
Michela Ripolone ◽  
Justin S Kolb ◽  
Mark Turmaine ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nuclear Envelope ◽  
Muscle Fibre ◽  
Nemaline Myopathy ◽  
Cytoskeletal Proteins ◽  
Muscle Fibres ◽  
Filament Structure ◽  
Transcriptional Alterations ◽  
Fibre Growth ◽  
Chromatin Arrangement

AbstractNemaline myopathy (NM) is a genetically heterogeneous skeletal muscle disorder caused by mutations predominately affecting contractile filaments, in particular thin filament structure and/or regulation. The underlying cellular pathophysiology of this disease remains largely unclear. Here, we report novel pathological defects in skeletal muscle fibres of mice and patients with NM, including disrupted nuclear envelope, altered chromatin arrangement, and disorganisation of the cortical cytoskeleton. We demonstrate that such nuclear defects are caused by impairment of muscle fibre contractility, and that cytoskeletal organisation determines nuclear morphology. Our results overlap with findings in diseases caused by mutations in nuclear envelope or cytoskeletal proteins. Given the important role of nuclear shape and envelope in regulating gene expression, and the cytoskeleton in maintaining muscle fibre integrity, our findings are likely to underlie some of the hallmarks of NM, which include broad transcriptional alterations, arrested muscle fibre growth, contractile filament disarray and altered mechanical properties.

scholarly journals Cellular Fate of Truncated Slow Skeletal Muscle Troponin T Produced by Glu180Nonsense Mutation in Amish Nemaline Myopathy

2005 ◽  
Vol 280 (14) ◽  
pp. 13241-13249 ◽  
Author(s):  
Xin Wang ◽  
Qi-Quan Huang ◽  
Mark T. Breckenridge ◽  
Aihua Chen ◽  
Thomas O. Crawford ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Troponin T ◽  
Nemaline Myopathy ◽  
Slow Skeletal Muscle ◽  
Cellular Fate

scholarly journals Truncation by Glu180Nonsense Mutation Results in Complete Loss of Slow Skeletal Muscle Troponin T in a Lethal Nemaline Myopathy

2003 ◽  
Vol 278 (28) ◽  
pp. 26159-26165 ◽  
Author(s):  
Jian-Ping Jin ◽  
Marco A. Brotto ◽  
M. Moazzem Hossain ◽  
Qi-Quan Huang ◽  
Leticia S. Brotto ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Troponin T ◽  
Nemaline Myopathy ◽  
Complete Loss ◽  
Slow Skeletal Muscle

scholarly journals Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy

2021 ◽  
Vol 7 (3) ◽  
pp. e589
Author(s):  
Daniel G. Calame ◽  
Jawid Fatih ◽  
Isabella Herman ◽  
Zeynep Coban Akdemir ◽  
Haowei Du ◽  
...  
Keyword(s):  
Troponin T ◽  
Nemaline Myopathy ◽  
Congenital Myopathy ◽  
Sequencing Data ◽  
Gene Encoding ◽  
Distal Arthrogryposis ◽  
Pathogenic Variants ◽  
Patient Reported ◽  
History Of ◽  
Nemaline Rods

ObjectivePathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants.MethodsClinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy.ResultsA homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here.ConclusionsThis report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.

scholarly journals A Reduction in Selenoprotein S Amplifies the Inflammatory Profile of Fast-Twitch Skeletal Muscle in themdxDystrophic Mouse

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Craig Robert Wright ◽  
Giselle Larissa Allsopp ◽  
Alex Bernard Addinsall ◽  
Natasha Lee McRae ◽  
Sofianos Andrikopoulos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Muscle Fibres ◽  
Muscle Fibre Size ◽  
Monocyte Chemoattractant Protein 1 ◽  
Selenoprotein S ◽  
Inflammatory Profile ◽  
Fast Twitch

Excessive inflammation is a hallmark of muscle myopathies, including Duchenne muscular dystrophy (DMD). There is interest in characterising novel genes that regulate inflammation due to their potential to modify disease progression. Gene polymorphisms inSelenoprotein S(Seps1) are associated with elevated proinflammatory cytokines, and in vitro SEPS1 is protective against inflammatory stress. Given that SEPS1 is highly expressed in skeletal muscle, we investigated whether the genetic reduction ofSeps1exacerbated inflammation in themdxmouse. F1 malemdxmice with a heterozygousSeps1deletion (mdx:Seps1−/+) were generated. Themdx:Seps1−/+mice had a 50% reduction in SEPS1 protein expression in hindlimb muscles. In the extensor digitorum longus (EDL) muscles, mRNA expression ofmonocyte chemoattractant protein 1(Mcp-1) (P=0.034), macrophage markerF4/80(P=0.030), andtransforming growth factor-β1(Tgf-β1) (P=0.056) were increased inmdx:Seps1−/+mice. This was associated with a reduction in muscle fibre size; however, ex vivo EDL muscle strength and endurance were unaltered. In dystrophic slow twitch soleus muscles, SEPS1 reduction had no effect on the inflammatory profile nor function. In conclusion, the genetic reduction ofSeps1appears to specifically exacerbate the inflammatory profile of fast-twitch muscle fibres, which are typically more vulnerable to degeneration in dystrophy.

scholarly journals Cardiac troponin I, cardiac troponin T, and creatine kinase MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle

1997 ◽  
Vol 43 (6) ◽  
pp. 976-982 ◽  
Author(s):  
Mary D McLaurin ◽  
Fred S Apple ◽  
Ellen M Voss ◽  
Charles A Herzog ◽  
Scott W Sharkey
Keyword(s):  
Skeletal Muscle ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Cardiac Troponin ◽  
First Generation ◽  
Troponin T ◽  
Ischemic Heart ◽  
Cardiac Troponin T ◽  
Dialysis Patients ◽  
Acute Ischemic Heart Disease

Abstract Serum cardiac troponin T (cTnT) concentrations are frequently increased in chronic dialysis patients as measured by the first-generation ELISA immunoassay, as is creatine kinase (CK) MB mass in the absence of acute ischemic heart disease. We designed this study to compare four serum markers of myocardial injury [CK-MB mass, first-generation ELISA cTnT, second-generation Enzymun cTnT, and cardiac troponin I (cTnI)] in dialysis patients without acute ischemic heart disease. We also evaluated skeletal muscle from dialysis patients as a potential source of serum cTnT. No patients in the clinical evaluation group (n = 24) studied by history and by physical examination, electrocardiography, and two-dimensional echocardiography had evidence of ischemic heart disease. Biochemical markers were measured in serial predialysis blood samples with specific monoclonal antibody-based immunoassays. For several patients at least one sample measured above the upper reference limit: CK-MB, 7 of 24 (30%); ELISA cTnT, 17 of 24 (71%); Enzymun cTnT, 3 of 18 (17%); and cTnI, 1 of 24 (4%). In a separate group of dialysis patients (n = 5), expression of cTnT, but not cTnI, was demonstrated by Western blot analysis in 4 of 5 skeletal muscle biopsies. Chronic dialysis patients without acute ischemic heart disease frequently had increased serum CK-MB and cTnT. The specificity of the second-generation cTnT (Enzymun) assay was improved over that of the first-generation (ELISA) assay; cTnI was the most specific of the currently available biochemical markers. cTnT, but not cTnI, was expressed in the skeletal muscle of dialysis patients.

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