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Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype–phenotype correlations

✍ Scribed by Jordan P. Lerner-Ellis; Natascia Anastasio; Junhui Liu; David Coelho; Terttu Suormala; Martin Stucki; Amanda D. Loewy; Scott Gurd; Elin Grundberg; Chantal F. Morel; David Watkins; Matthias R. Baumgartner; Tomi Pastinen; David S. Rosenblatt; Brian Fowler

Publisher
John Wiley and Sons
Year
2009
Tongue
English
Weight
218 KB
Volume
30
Category
Article
ISSN
1059-7794

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✦ Synopsis

Methylmalonic aciduria and homocystinuria, cblC type, is a rare disorder of intracellular vitamin B 12 (cobalamin [Cbl]) metabolism caused by mutations in the MMACHC gene. MMACHC was sequenced from the gDNA of 118 cblC individuals. Eleven novel mutations were identified, as well as 23 mutations that were observed previously. Six sequence variants capture haplotype diversity in individuals across the MMACHC interval. Genotype-phenotype correlations of common mutations were apparent; individuals with c.394C4T tend to present with late-onset disease whereas patients with c.331C4T and c.271dupA tend to present in infancy. Other missense variants were also associated with late-or early-onset disease. Allelic expression analysis was carried out on human cblC fibroblasts compound heterozygous for different combinations of mutations including c.271dupA, c.331C4T, c.394C4T, and c.482G4A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C4T and c.482G4A mutations. The early-onset c.331C4T mutation was also underexpressed when compared to control alleles and the c.394C4T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C4T, and c.394C4T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C4T mutation had significantly higher levels of transcript when compared to cell lines homozygous for the early-onset mutations. Differential or preferential MMACHC transcript levels may provide a clue as to why individuals carrying c.394C4T generally present later in life.

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