期刊
GENES
卷 8, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/genes8100253
关键词
Becker muscular dystrophy; cDNA; DMD; Dystrophin; LINE-1
资金
- UMIB - Fundacao para a Ciencia e Tecnologia (FCT) [Pest-OE/SAU/UI0215/2014]
- Fundo para a Investigacao e Desenvolvimento do Centro Hospitalar do Porto [336-13(196-DEFI/285-CES)]
- Fundação para a Ciência e a Tecnologia [PEst-OE/SAU/UI0215/2014] Funding Source: FCT
A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (similar to 6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD.
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