Journal
MOLECULAR GENETICS & GENOMIC MEDICINE
Volume 10, Issue 6, Pages -Publisher
WILEY
DOI: 10.1002/mgg3.1934
Keywords
DKC1; intron retention; intronic mutation; minigene splicing assay
Categories
Funding
- Shanghai municipal science and technology major project [20Z11900600]
- Shanghai municipal science and technology [18411962000]
- Shanghai Key Laboratory of Birth Defects [13DZ2260600]
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We reported a novel intronic mutation of DKC1 causing dyskerin functional loss in a Chinese family. This mutation may influence normal physiological function and is associated with still birth or early death. The finding expands the spectrum of pathogenic DKC1 gene mutations and can be used in molecular diagnosis.
Background: DKC1, the dyskerin encoding gene, functions in telomerase activity and telomere maintenance. DKC1 mutations cause a multisystem disease, dyskeratosis congenita (DC), which is associated with immunodeficiency and bone marrow failure. Methods: In this research, we reported a novel intronic mutation of DKC1 causing dyskerin functional loss in a Chinese family. Whole exome sequence (WES) of the proband and validation by ranger sequencing help us identify a pathogenic DKC1 mutation. Minigene splicing assays were performed to evaluate functional change of DKC1. Results: A pathogenic DKC1 intronic mutation(c.84 + 7A > G) was identified in the proband, which was inherited from heterozygous mother and not reported before. We detected the novel transcript with a 7 bp intron retention through minigene splicing assay. The newly spliced transcript is so short that would be degraded by nonsense-mediated mRNA decay in vitro and we infer that the novel DKC1 mutation would influences normal physiological function of dyskerin. Conclusions: Our study identified a novel intronic mutation, which expands the spectrum of pathogenic DKC1 gene mutations and can be used in molecular diagnosis. The mutant allele was transmitted to the next generation with high frequency in the family and causes still birth or early death.
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