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MUT, IVS11, C-A, -891 AND METHYLMALONIC ACIDURIA, mut(0) TYPE

Significance: Pathogenic
ClinVar: RCV000001966

Variant: MUT, IVS11, C-A, -891

Type: Variant
Allele: MUT, IVS11, C-A, -891 16928
Gene:
Type: single nucleotide variant
References: OMIM: 609058.0013

Condition

Disease: METHYLMALONIC ACIDURIA, mut(0) TYPE

Citation

    Rincon et al. (2007) studied a patient with mut MMA (251000) who had been found by Martinez et al. (2005) to have a 76-bp insertion between exons 11 and 12 corresponding to an exon-like region in intron 11 (1957ins76). Rincon et al. (2007) found that the patient's DNA contained a C-to-A change in intron 11 at position +7 relative to the inserted sequence (IVS11-891C-A). Experimental confirmation that the change was pathogenic and caused the activation of the pseudoexon was obtained by use of a minigene. Rincon et al. (2007) used antisense morpholino oligonucleotides (AMOs) to target a cryptic splice site to block access of the splicing machinery in the pseudoexonic region in the pre-mRNA. Using this antisense therapeutics, they obtained correctly spiced mRNA that was effectively translated, and methylmalonyl CoA mutase (MCM) activity was rescued in the patients' fibroblasts. The effect of the AMO was sequence- and dose-dependent. Close to 100% of MCM activity, measured by incorporation of (14)C-propionate, was obtained after 48 hours, and correctly spliced MUT mRNA was still detected 15 days after treatment. The patient with MUT deficiency studied by Rincon et al. (2007) was compound heterozygous for the intronic insertion and a splicing mutation in the last nucleotide of exon 10 (1808G-A; 609058.0014), and had 2 aberrant transcripts as a result of the use of cryptic splice sites.
PMID:15781192, PMID:17966092