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Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type

An Erratum to this article was published on 01 August 2006

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Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings1. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood2. The cblC locus was mapped to chromosome region 1p by linkage analysis3. We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

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Figure 1: MMACHC location, structure and mutations.
Figure 2: Transduction of fibroblast cells with MMACHC.
Figure 3: Haplotypes inferred from 54 CEPH individuals and from 99 cblC individuals homozygous for MMACHC mutations.
Figure 4: Conservation and homology-based modeling of MMACHC.

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  • 30 June 2006

    The error has been corrected in the PDF version of this article.


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We dedicate this work to the memory of J.C. Tirone. We thank the clinicians who provided patient samples and clinical information; N. Matiaszuk and J. Lavallée for complementation analysis; A. Verner and G. Genaud for microsatellite genotyping; N. Roslin for microsatellite analysis; M. Galvez and J. Liu for laboratory work; G. Leveque, T.A. Johns and D. Roquis for technical assistance; S. Froese, L. Worgan, K. Niles and A. Montpetit for discussion and J. Kashul and D. Ellis for editing. This research was supported by grants from the March of Dimes Birth Defects Foundation (6-FY01-11), Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation to the Montreal Integrated Genomics Group for Research on Infectious Pathogens, and the Network of Centres of Excellence Program—the Canadian Genetic Diseases Network. D.S.R. is a principal investigator in the CIHR Group in Medical Genetics. This is a publication of the Hess B. and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone.

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Correspondence to David S Rosenblatt.

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Supplementary information

Supplementary Fig. 1

One affected child and one affected fetus were diagnosed with cblC. (PDF 250 kb)

Supplementary Table 1

Markers used for homozygosity mapping and haplotype analyses. (PDF 15 kb)

Supplementary Table 2

Primers used to amplify the MMACHC gene from gDNA and cDNA. (PDF 54 kb)

Supplementary Note (PDF 36 kb)

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Lerner-Ellis, J., Tirone, J., Pawelek, P. et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38, 93–100 (2006).

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