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

Published on Sep 1, 2021in Journal of Medical Genetics4.943
· DOI :10.1136/JMEDGENET-2019-106714
Justine Géraud1
Estimated H-index: 1
Klaus Dieterich15
Estimated H-index: 15
(University of Toulouse)
+ 19 AuthorsClaude Cances19
Estimated H-index: 19
Background Congenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres. Methods Using 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. Results The 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. Discussion The 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.
#1Kentaro Oki (WSU: Wayne State University)H-Index: 1
#2Bin Wei (WSU: Wayne State University)H-Index: 4
Last. Jian Ping Jin (WSU: Wayne State University)H-Index: 43
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KEY POINTS: The pathogenic mechanism and the neuromuscular reflex-related phenotype (e.g. tremors accompanied by clonus) of Amish nemaline myopathy, as well as of other recessively inherited TNNT1 myopathies, remain to be clarified. The truncated slow skeletal muscle isoform of troponin T (ssTnT) encoded by the mutant TNNT1 gene is unable to incorporate into myofilaments and is degraded in muscle cells. By contrast to extrafusal muscle fibres, spindle intrafusal fibres of normal mice contain a s...
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Nemaline myopathies are a heterogenous group of congenital myopathies caused by de novo, dominantly or recessively inherited mutations in at least twelve genes. The genes encoding skeletal α-actin (ACTA1) and nebulin (NEB) are the commonest genetic cause. Most patients have congenital onset characterized by muscle weakness and hypotonia, but the spectrum of clinical phenotypes is broad, ranging from severe neonatal presentations to onset of a milder disorder in childhood. Most patients with adul...
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Abstract Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according...
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Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients’ muscle biopsies. We defined “dusty cores” the irregular areas of myofibrillar disorganisation character...
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: We describe the natural history of 'Amish' nemaline myopathy (ANM), an infantile-onset, lethal disease linked to a pathogenic c.505G>T nonsense mutation of TNNT1, which encodes the slow fiber isoform of troponin T (TNNT1; a.k.a. TnT). The TNNT1 c.505G>T allele has a carrier frequency of 6.5% within Old Order Amish settlements of North America. We collected natural history data for 106 ANM patients born between 1923 and 2017. Over the last two decades, mean age of molecular diagnosis was 16 ± 2...
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#1Reda ZenaguiH-Index: 2
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Myopathies and muscular dystrophies (M-MDs) are genetically heterogeneous diseases, with >100 identified genes, including the giant and complex titin ( TTN ) and nebulin ( NEB ) genes. Next-generation sequencing technology revolutionized M-MD diagnosis and revealed high frequency of TTN and NEB variants. We developed a next-generation sequencing diagnostic strategy targeted to the coding sequences of 135 M-MD genes. Comparison of two targeted capture technologies (SeqCap EZ Choice library captur...
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#1Chamindra G. Konersman (UCSD: University of California, San Diego)H-Index: 4
#2Fernande Freyermuth (Harvard University)H-Index: 9
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BACKGROUND: Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historica...
15 CitationsSource
Nemaline myopathy (NM) is among the most common non-dystrophic congenital myopathies (incidence 1:50.000). Hallmark features of NM are skeletal muscle weakness and the presence of nemaline bodies in the muscle fiber. The clinical phenotype of NM patients is quite diverse, ranging from neonatal death to normal lifespan with almost normal motor function. As the respiratory muscles are involved as well, severely affected patients are ventilator-dependent. The mechanisms underlying muscle weakness i...
28 CitationsSource
#1Edoardo Malfatti (French Institute of Health and Medical Research)H-Index: 21
#2Norma B. Romero (French Institute of Health and Medical Research)H-Index: 59
Abstract Nemaline myopathy (NM) is one of the most common forms of congenital myopathy. The condition is defined by the histopathological finding of nemaline bodies (rods) on muscle biopsy and is associated with hypotonia and muscle weakness. The clinical spectrum encompasses lethal forms presenting in the neonatal period with profound weakness and less severe congenital diseases of later onset. NM is significantly heterogeneous from a genetic point of view, and its inheritance can be autosomal-...
31 CitationsSource
#1Chinthaka Amarasinghe (WSU: Wayne State University)H-Index: 3
#2M. Moazzem Hossain (WSU: Wayne State University)H-Index: 12
Last. Jian Ping Jin (WSU: Wayne State University)H-Index: 43
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Troponin T (TnT) is the tropomyosin (Tm)-binding and thin filament-anchoring subunit of troponin and plays a central role in striated muscle contraction. A nonsense mutation in exon 11 of the TNNT1 gene encoding slow skeletal muscle troponin T (ssTnT) truncating the polypeptide chain at Glu180 causes a lethal recessive nemaline myopathy (NM) in the Amish (ANM). More TNNT1 NM mutations have been reported recently with similar recessive phenotypes. A nonsense mutation in exon 9 causes truncation a...
15 CitationsSource
Cited By4
#2Jian Ping Jin (WSU: Wayne State University)H-Index: 43
#1Daniel G. Calame (BCM: Baylor College of Medicine)H-Index: 2
#2Jawid M Fatih (Boston Children's Hospital)H-Index: 6
Last. James R. LupskiH-Index: 146
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Objective Pathogenic 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. Methods Clinical exome sequencing data from a patient with molecularly undiagnosed congenital...
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