LAMA2 mRNA processing alterations generate a complete deficiency of laminin-α2 protein and a severe congenital muscular dystrophy

Siala, Olfa; Louhichi, Nacim; Triki, Chahnez; Morinière, Madeleine; Fakhfakh, Faïza; Baklouti, Faouzi

doi:10.1016/j.nmd.2007.09.003

Cited by 15 publications

(6 citation statements)

References 34 publications

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“…On the other hand, c.6085+12delA may disrupt base pairing between the donor splicing consensus of intron 42 of LAMA2 pre mRNA and the 5' end of U1snRNA, this recognition being crucial for U6snRNP recruitment (Lund and Kjems, 2002). The importance of this region was also confirmed in our previous studies which demonstrated that a 7 bp deletion from position +5 to +11 in the donor splicing consensus of intron 17 of the LAMA2 gene triggered total skipping of exon 17 (Siala et al , 2008). Moreover, the position +12 in the 5' splicing consensus has already been demonstrated to be determinant for the correct mRNA processing of the ATM gene through its interaction with the U1snRNA (Lewandowska et al , 2005).…”

Section: Discussionsupporting

confidence: 74%

Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

et al. 2010

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In this study, we detected new sequence variations in LAMA2 and SGCG genes in 5 ethnic populations, and analysed their effect on enhancer composition and mRNA structure. PCR amplification and DNA sequencing were performed and followed by bioinformatics analyses using ESEfinder as well as MFOLD software. We found 3 novel sequence variations in the LAMA2 (c.3174+22_23insAT and c.6085 +12delA) and SGCG (c. * 102A/C) genes. These variations were present in 210 tested healthy controls from Tunisian, Moroccan, Algerian, Lebanese and French populations suggesting that they represent novel polymorphisms within LAMA2 and SGCG genes sequences. ESEfinder showed that the c. * 102A/C substitution created a new exon splicing enhancer in the 3'UTR of SGCG genes, whereas the c.6085 +12delA deletion was situated in the base pairing region between LAMA2 mRNA and the U1snRNA spliceosomal components. The RNA structure analyses showed that both variations modulated RNA secondary structure. Our results are suggestive of correlations between mRNA folding and the recruitment of spliceosomal components mediating splicing, including SR proteins. The contribution of common sequence variations to mRNA structural and functional diversity will contribute to a better study of gene expression.

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Section: Discussionsupporting

confidence: 74%

Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

et al. 2010

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“…At this time, it is believed that up to 15% of genetic diseases may be caused by intronic mutations 29 30 Case reports of patients with deep intronic or other complex pathogenic mutations, proven with messenger RNA analysis and other in vitro studies, are becoming more recognized and have been reported in genes such as LAMA2 , 31 DOK7, 32 and others 33 34 RNA sequencing from the muscle tissue of patients with undiagnosed muscular dystrophy is likely to provide a significantly higher diagnostic yield than NGS (panels and whole exome sequencing), though is not yet as widely available 35 .…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia

Brady

Shoffner

et al. 2018

Can. J. Neurol. Sci.

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This study shows that NGS can be a useful tool in the molecular workup of patients seen in a neuromuscular clinic. Evaluating the utility of large panels of a muscle disease-specific NGS panel to investigate the genetic susceptibilities of rhabdomyolysis and/or idiopathic hyperCKemia is a relatively new field. Twenty-eight of the pathogenic and likely pathogenic variants reported here are novel and have not previously been associated with disease.

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“…however, siala et al 96,97 have emphasized the utility of mrNA analysis in cases of MDC 1A to understand the mechanism of the mutation and the genotype-phenotype correlation. recently, also oliveira et al 98 emphasized the utility of analyzing genotype/phenotype correlations in MDC1A.…”

Section: Merosin-deficient Congenital Muscular Dystrophy: Mdc1amentioning

confidence: 99%

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

Reed

2009

Arq. Neuro-Psiquiatr.

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-The congenital muscular dystrophies (CMDs) are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem), CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscleeye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D), and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.Key WorDs: congenital muscular dystrophy, MDC1A, collagen VI related disorders, glycosylation of alphadystroglycan, Fukuyama DMC, muscle-eye-brain (MeB) disease, Walker-Warburg syndrome, rigid spine syndrome. distrofia muscular congênita. parte ii: revisão da patogênese e perspectivas terapêuticas resumo -As distrofias musculares congênitas (DMCs) são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. são caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. o quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. os aspectos clínicos e diagnósticos dos principais subtipos de DMC foram apresentados no número anterior deste periódico, como primeira parte desta revisão. Nesta segunda parte apresentaremos os principais mecanismos patogênicos e as perspectivas terapêuticas dos subtipos mais comuns de DMC: DMC tipo 1A com deficiência de merosina, DMCs relacionadas com alterações do colágeno VI (Ullrich e Bethlem), e DMCs com anormalidades de glicosilação da alfa-distroglicana (DMC Fukuyama, DMC "Muscle-eye-brain" ou MeB, síndrome de Walker Warburg, DMC tipo 1C, DMC tipo 1D). A DMC com espinha rígida, mais rara e não relacionada com alterações do complexo distrofina-glicoproteínas associadas-matriz extracelular também será abordada quanto aos mesmos aspectos patogênicos e terapêuticos.PAlAVrAs-ChAVes: distrofia muscular congênita, merosina, colágeno VI, glicosila...

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LAMA2 mRNA processing alterations generate a complete deficiency of laminin-α2 protein and a severe congenital muscular dystrophy

Cited by 15 publications

References 34 publications

Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

Novel sequence variations in LAMA2 and SGCG genes modulating cis-acting regulatory elements and RNA secondary structure

Next-Generation Sequencing to Diagnose Muscular Dystrophy, Rhabdomyolysis, and HyperCKemia

Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives

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