Clinical utility gene card for: Centronuclear and myotubular myopathies

Biancalana, Valérie; Beggs, Alan H.; Das, Soma; Jungbluth, Heinz; Kreß, Wolfram; Nishino, Ichizo; North, Klaus; Romero, Norma B.; Laporte, Jocelyn

doi:10.1038/ejhg.2012.91

Cited by 28 publications

(28 citation statements)

References 38 publications

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“…During routine MTM1 gDNA sequencing in P2, no symmetrical PCR amplification was obtained for the majority of exons (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). This led us to suspect the presence of a large intragenic deletion, which was subsequently confirmed by MLPA (Supplementary Figure S5a).…”

Section: Mtm1-lovdmentioning

confidence: 98%

“…1,2 In CNM, the most prominent histopathological features include hypotrophy of type 1 fibers and a high frequency of centrally located nuclei with perinuclear halos lacking myofilaments and occupied by mitochondrial and glycogen aggregates. 1 Several genes are reported to be associated with CNM; these include MTM1 in the X-linked form, 3,4 DNM2 and MTMR14 in the autosomal dominant forms, [4][5][6] BIN1 and RYR1 associated with the autosomal recessive forms. 4,[7][8][9] X-linked myotubular myopathy (XLMTM; MIM 310400) has a prevalence of approximately 1/50 000 males and is characterized by severe hypotonia present at birth and inability to maintain sustained spontaneous respiration.…”

Section: Introductionmentioning

confidence: 99%

“…1 Several genes are reported to be associated with CNM; these include MTM1 in the X-linked form, 3,4 DNM2 and MTMR14 in the autosomal dominant forms, [4][5][6] BIN1 and RYR1 associated with the autosomal recessive forms. 4,[7][8][9] X-linked myotubular myopathy (XLMTM; MIM 310400) has a prevalence of approximately 1/50 000 males and is characterized by severe hypotonia present at birth and inability to maintain sustained spontaneous respiration. 10 Different authors have proposed that patients be classified according to their phenotype, as: (i) severecharacteristic facial features, markedly delayed motor milestones and requiring prolonged ventilatory support (412 h); (ii) moderatemore rapid acquirement of motor milestones and independent respiration for 412 h per day; (iii) mild -motor milestones slightly delayed and independent spontaneous respiratory function achieved after the neonatal period.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Oliveira

Kreß

et al. 2012

Eur J Hum Genet

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Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin -a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligationdependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.

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Section: Mtm1-lovdmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Oliveira

Kreß

et al. 2012

Eur J Hum Genet

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“…CNMs are unified by common histopathologic features on muscle biopsy, most notably the presence of large, centrally located nuclei in at least 10% (and often in excess of 25%) of muscle fibers [41]. CNMs can be further subdivided into groups based on genetic cause [42]. The most common genetic cause is mutations in myotubularin (encoded by MTM1).…”

Section: Cnmsmentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

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The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.

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“…To date, mutations in 4 genes involved in either the assembly or function of triads, the specialized membrane structures sustaining the excitation-contraction coupling, 4 have been identified in CNM patients: MTM1 (myotubularin) in X-linked severe CNM (MIM 310400), DNM2 (dynamin 2) in autosomal dominant and sporadic cases (MIM 160150), BIN1 (amphiphysin 2) causing rare autosomal recessive disease (MIM 255200), and RYR1 (ryanodine receptor 1) associated with autosomal recessive and sporadic presentations. 5 Nevertheless, the genetic basis for disease remains unknown in a significant proportion of patients with clinicopathologic diagnoses of CNM (;20%), 5 hampering a complete understanding of the molecular mechanisms underlying the pathogenesis and genetic counseling in such families. To identify additional genes involved in these conditions, we performed whole-exome sequencing, or in one case whole-genome sequencing, on DNA from a cohort of 29 unrelated patients who presented to the research study with clinicopathologic diagnoses of CNM.…”

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confidence: 99%

Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

et al. 2013

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Objective: To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and hypotonia, using next-generation sequencing of whole exomes and genomes.Methods: Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest.Results: Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations.Conclusions: Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.

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Clinical utility gene card for: Centronuclear and myotubular myopathies

Cited by 28 publications

References 38 publications

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Recessive truncating titin gene, TTN , mutations presenting as centronuclear myopathy

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