Genotype–phenotype correlations in X-linked myotubular myopathy

McEntagart, Meriel; Parsons, Gretchen; Buj‐Bello, Anna; Biancalana, Valérie; Fenton, I.; Little, Mark A.; Krawczak, Michael; Thomas, Nick; Herman, Gail E.; Clarke, Angus; Wallgren‐Pettersson, Carina

doi:10.1016/s0960-8966(02)00153-0

Cited by 128 publications

(181 citation statements)

References 19 publications

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“…In a previous study, 12 the analysis of a large number of patients revealed a statistically significant association between non-truncating mutations and the mild phenotype, as opposed to the intermediate/ severe phenotype associated with mutations that give rise to PTC. We performed a similar analysis of all data available in MTM1-LOVD with the aim of obtaining further correlation between genotype and phenotype.…”

Section: Database Content Analysismentioning

confidence: 84%

“…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%

“…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. 11,12 Carrier females are usually asymptomatic, however there are several records of manifesting heterozygotes due to skewed X chromosome inactivation. [13][14][15][16][17][18] The MTM1 gene (in Xq28) is composed of 15 exons and has an open reading frame of 1.8 kb encoding the myotubularin protein.…”

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: Database Content Analysismentioning

confidence: 84%

Section: Mtm1-lovdmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…4 The natural history of specific subgroups has been described in only a few cohorts, not all of which had been fully genetically characterized. 5,[13][14][15][16][17][18][19] Herein, we report the clinical course of 125 patients with CM, reviewed at a single neuromuscular center. Furthermore, genotypephenotype correlations in a subgroup of 99 genetically characterized cases are illustrated.…”

mentioning

confidence: 99%

Congenital myopathies

et al. 2015

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Objective: To assess the natural history of congenital myopathies (CMs) due to different genotypes. Methods:Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012.Results: Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p 5 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchairdependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years). Conclusions:We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling. Neurology ® 2015;84:28-35 GLOSSARY ACTA1 5 skeletal muscle a-actin; AD 5 autosomal dominant; AR 5 autosomal recessive; CM 5 congenital myopathy; CNM 5 centronuclear myopathy; DNIV 5 daily noninvasive ventilation; DNM2 5 dynamin 2; FTD 5 fiber type disproportion; G/J 5 gastrostomy/jejunostomy; KLHL40 5 kelch-like family member 40; MTM1 5 myotubularin; NEB 5 nebulin; NGT 5 nasogastric tube; NM 5 nemaline myopathy; NNIV 5 nocturnal noninvasive ventilation; NSMC 5 nonspecific myopathic changes; RYR1 5 ryanodine receptor type 1; SEPN1 5 selenoprotein N; TPM2 5 b-tropomyosin; TPM3 5 tropomyosin 3.

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“…10 To date, some MTM1 mutations were shown to have an impact on splicing and the majority of patients with splice site mutations presented with a severe phenotype, although a few cases show mild or moderate phenotypes. [4][5][6][7]11 In muscle and lymphoblastoid cells from the patient described in the present study, the majority of the analyzed MTM1 cDNAs is predicted to lead either to the absence of the starting methionine in exon 2 or to the disruption of the coding frame. Indeed MTM1 protein level was strongly decreased although a weak normal sized band was detected when overloading the patient sample (not shown), probably sustaining the mild phenotype.…”

Section: Discussionmentioning

confidence: 79%

Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype

et al. 2012

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Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT-PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases.

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Genotype–phenotype correlations in X-linked myotubular myopathy

Cited by 128 publications

References 19 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

Congenital myopathies

Myotubular myopathy caused by multiple abnormal splicing variants in the MTM1 RNA in a patient with a mild phenotype

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