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

Lerner-Ellis, Jordan P. and Anastasio, Natascia and Liu, Junhui and Coelho, David and Suormala, Terttu and Stucki, Martin and Loewy, Amanda D. and Gurd, Scott and Grundberg, Elin and Morel, Chantal F. and Watkins, David and Baumgartner, Matthias R. and Pastinen, Tomi and Rosenblatt, David S. and Fowler, Brian. (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Human mutation, Vol. 30, no. 7. pp. 1072-1081.

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Official URL: http://edoc.unibas.ch/dok/A5253666

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Abstract

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.394C<T tend to present with late-onset disease whereas patients with c.331C<T 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.331C<T, c.394C<T, and c.482G<A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C<T and c.482G<A mutations. The early-onset c.331C<T mutation was also underexpressed when compared to control alleles and the c.394C<T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C<T, and c.394C<T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C<T 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.394C<T generally present later in life.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Ehemalige Einheiten Pädiatrie (UKBB) > Labor (Fowler)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Ehemalige Einheiten Pädiatrie (UKBB) > Labor (Fowler)
03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrie (Frey)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrie (Frey)
UniBasel Contributors:Fowler, Brian
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Wiley-Liss
ISSN:1098-1004
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Feb 2013 08:45
Deposited On:22 Mar 2012 13:39

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