DMD mutations in 576 dystrophinopathy families : A step forward in genotype-phenotype correlations
Juan-Mateu, Jonas (Institut d'Investigació Biomèdica Sant Pau)
Gonzalez Quereda, Lídia (Institut d'Investigació Biomèdica Sant Pau)
Rodriguez, María José (Institut d'Investigació Biomèdica Sant Pau)
Baena, Manel (Institut d'Investigació Biomèdica Sant Pau)
Verdura, Edgard (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Nascimento, Andres (Hospital Sant Joan de Déu (Esplugues de Llobregat, Catalunya))
Ortez, Carlos (Hospital Sant Joan de Déu (Esplugues de Llobregat, Catalunya))
Baiget Bastús, Montserrat (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Gallano, Pia (Institut d'Investigació Biomèdica Sant Pau)
Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia

Data:	2015
Resum:	Recent advances in molecular therapies for Duchenne muscular dystrophy (DMD) require precise genetic diagnosis because most therapeutic strategies are mutation-specific. To understand more about the genotype-phenotype correlations of the DMD gene we performed a comprehensive analysis of the DMD mutational spectrum in a large series of families. Here we provide the clinical, pathological and genetic features of 576 dystrophinopathy patients. DMD gene analysis was performed using the MLPA technique and whole gene sequencing in blood DNA and muscle cDNA. The impact of the DNA variants on mRNA splicing and protein functionality was evaluated by in silico analysis using computational algorithms. DMD mutations were detected in 576 unrelated dystrophinopathy families by combining the analysis of exonic copies and the analysis of small mutations. We found that 471 of these mutations were large intragenic rearrangements. Of these, 406 (70. 5%) were exonic deletions, 64 (11. 1%) were exonic duplications, and one was a deletion/duplication complex rearrangement (0. 2%). Small mutations were identified in 105 cases (18. 2%), most being nonsense/frameshift types (75. 2%). Mutations in splice sites, however, were relatively frequent (20%). In total, 276 mutations were identified, 85 of which have not been previously described. The diagnostic algorithm used proved to be accurate for the molecular diagnosis of dystrophinopathies. The reading frame rule was fulfilled in 90. 4%of DMD patients and in 82. 4% of Becker muscular dystrophy patients (BMD), with significant differences between the mutation types. We found that 58% of DMD patients would be included in single exon-exon skipping trials, 63% from strategies directed against multiexon-skipping exons 45 to 55, and 14% from PTC therapy. A detailed analysis of missense mutations provided valuable information about their impact on the protein structure.
Ajuts:	Ministerio de Ciencia e Innovación PI11/02586
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Dystrophin ; Female ; Genotype ; Humans ; Male ; Muscular Dystrophy, Duchenne ; Mutation ; Pedigree ; Phenotype
Publicat a:	PloS one, Vol. 10 Núm. 8 (18 2015) , p. e0135189, ISSN 1932-6203

DOI: 10.1371/journal.pone.0135189
PMID: 26284620

21 p, 2.3 MB

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