Identification of novel mutations in theMTM1 gene causing severe and mild forms of X-linked myotubular myopathy

Buj‐Bello, Anna; Biancalana, Valérie; Moutou, Céline; Laporte, Jocelyn; Mandel, Jean‐Louis

doi:10.1002/(sici)1098-1004(199910)14:4<320::aid-humu7>3.0.co;2-o

Cited by 42 publications

(26 citation statements)

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“…Patients 8 and 9 are brothers ( Table 1). Eight of the 15 XLMTM patients are described for the first time and for seven of the 15 patients the molecular defects have been reported previously (Table 2) (Laporte et al 1997;Buj-Bello et al 1999;Biancalana et al 2003). Prenatal diagnosis was not made for any patient.…”

Section: Patientsmentioning

confidence: 99%

“…tions were detected in the mother's and the affected brother's DNA, respectively. DNAs were studied by direct sequencing of exons and intron-exon boundaries of the MTM1 gene as previously described (Buj-Bello et al 1999). For patients 5 and 11, a deletion was detected and confirmed by MLPA analysis (kit P309, MRC-Holland, Amsterdam, the Netherlands) ( Table 2).…”

Section: Molecular Studiesmentioning

confidence: 99%

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Extensive morphological and immunohistochemical characterization in myotubular myopathy

et al. 2013

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The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM1-mutations according to the “adjusted-age” at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.

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Section: Patientsmentioning

confidence: 99%

Section: Molecular Studiesmentioning

confidence: 99%

Extensive morphological and immunohistochemical characterization in myotubular myopathy

et al. 2013

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“…Most XLMTM patients die at an average age of 4-8 months as a consequence of respiratory failure (1), although Ϸ15% of cases can survive for several years with a milder phenotype (2)(3)(4). Histopathological studies of the skeletal muscle in these patients reveal the presence of small rounded muscle fibers that contain centrally located nuclei surrounded by a halo devoid of myofibrils where mitochondria accumulate (5,6).…”

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confidence: 99%

The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice

Buj‐Bello

Laugel

Messaddeq

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Myotubularin is a ubiquitously expressed phosphatase that acts on phosphatidylinositol 3-monophosphate [PI(3)P], a lipid implicated in intracellular vesicle trafficking and autophagy. It is encoded by the MTM1 gene, which is mutated in X-linked myotubular myopathy (XLMTM), a muscular disorder characterized by generalized hypotonia and muscle weakness at birth leading to early death of most affected males. The disease was proposed to result from an arrest in myogenesis, as the skeletal muscle from patients contains hypotrophic fibers with centrally located nuclei that resemble fetal myotubes. To understand the physiopathological mechanism of XLMTM, we have generated mice lacking myotubularin by homologous recombination. These mice are viable, but their lifespan is severely reduced. They develop a generalized and progressive myopathy starting at around 4 weeks of age, with amyotrophy and accumulation of central nuclei in skeletal muscle fibers leading to death at 6 -14 weeks. Contrary to expectations, we show that muscle differentiation in knockout mice occurs normally. We provide evidence that fibers with centralized myonuclei originate mainly from a structural maintenance defect affecting myotubularin-deficient muscle rather than a regenerative process. In addition, we demonstrate, through a conditional gene-targeting approach, that skeletal muscle is the primary target of murine XLMTM pathology. These mutant mice represent animal models for the human disease and will be a valuable tool for understanding the physiological role of myotubularin.

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“…The most common and severe CNM is X‐linked myotubular myopathy (XLMTM), a disorder characterized by a deficiency of the phosphatase, myotubularin. Most affected newborns present with profound generalized weakness and typically require immediate mechanical ventilatory support . Although mortality approaches 50% within the first 18 months of life, the disease is thought to be non‐progressive in surviving children .…”

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Respiratory motor function in individuals with centronuclear myopathies

et al. 2015

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Introduction Individuals with X-linked myotubular myopathy (XLMTM) and other centronuclear myopathies (CNMs) frequently have profound respiratory insufficiency that requires support early in life. Still, few quantitative data exist to characterize respiratory motor function in CNM. Methods We evaluated the reliance upon mechanical ventilation (MV), ventilatory kinematics, unassisted tidal volumes, and maximal respiratory pressures in 14 individuals with CNMs, including 10 boys with XLMTM. Results Thirteen participants required full-time, invasive MV. Maximal inspiratory pressures were higher in subjects who breathed unsupported at least 1 hour per day than 24-hour MV users [33.7 (11.9–42.3) vs 8.4 (6.0–10.9) cm H2O, P<0.05]. Years of MV dependence significantly correlated with MEP (r=−0.715, P<0.01). Discussion Respiratory function in CNMs may be related to deconditioning from prolonged MV and/or differences in residual respiratory muscle strength. Results from this study may assist in evaluating severe respiratory insufficiency in neuromuscular clinical care and research.

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Identification of novel mutations in theMTM1 gene causing severe and mild forms of X-linked myotubular myopathy

Cited by 42 publications

References 19 publications

Extensive morphological and immunohistochemical characterization in myotubular myopathy

Extensive morphological and immunohistochemical characterization in myotubular myopathy

The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice

Respiratory motor function in individuals with centronuclear myopathies

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