Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Genetics volume 38, pages 93–100 (2006)Cite this article

An Erratum to this article was published on 01 August 2006

This article has been updated

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Protein Data Bank

Change history

  • 30 June 2006

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

References

  1. Rosenblatt, D. & Fenton, W.A. Inherited disorders of folate and cobalamin transport and metabolism in The Metabolic & Molecular Bases of Inherited Disease Vol. 3, 3897–3933 (McGraw-Hill, New York, 2001).

    Google Scholar 

  2. Rosenblatt, D.S. et al. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J. Inherit. Metab. Dis. 20, 528–538 (1997).

    Article  CAS  Google Scholar 

  3. Atkinson, J. Genetic Mapping of Cobalamin C Deficiency: Linkage to Chromosome 1p32–34. Thesis. Univ. of Toronto, (2003).

    Google Scholar 

  4. Homocysteine in Health and Disease (eds. Carmel, R. & Jacobsen, D.W.) (Cambridge Univ. Press, Cambridge, 2001).

  5. Andersson, H.C. & Shapira, E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J. Pediatr. 132, 121–124 (1998).

    Article  CAS  Google Scholar 

  6. Mellman, I., Willard, H.F., Youngdahl-Turner, P. & Rosenberg, L.E. Cobalamin coenzyme synthesis in normal and mutant fibroblasts: evidence for a processing enzyme activity deficient in cblC cells. J. Biol. Chem. 254, 11847–11853 (1979).

    CAS  PubMed  Google Scholar 

  7. Templeton, A.R. et al. Recombinational and mutational hotspots within the human lipoprotein lipase gene. Am. J. Hum. Genet. 66, 69–83 (2000).

    Article  CAS  Google Scholar 

  8. Stephens, M., Smith, N.J. & Donnelly, P. A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989 (2001).

    Article  CAS  Google Scholar 

  9. Stephens, M. & Donnelly, P. A comparison of Bayesian methods for haplotype reconstruction. Am. J. Hum. Genet. 73, 1162–1169 (2003).

    Article  CAS  Google Scholar 

  10. Maquat, L.E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat. Rev. Mol. Cell Biol. 5, 89–99 (2004).

    Article  CAS  Google Scholar 

  11. Drennan, C.L., Huang, S., Drummond, J.T., Matthews, R.G. & Ludwig, M.L. How a protein binds B12: a 3.0 A X-ray structure of B12 -binding domains of methionine synthase. Science 266, 1669–1674 (1994).

    Article  CAS  Google Scholar 

  12. Chang, C., Mooser, A., Plückthun, A. & Wlodawer, A. Crystal structure of the dimeric C-terminal domain of TonB reveals a novel fold. J. Biol. Chem. 276, 27535–27540 (2001).

    Article  CAS  Google Scholar 

  13. Ködding, J. et al. Crystal structure of a 92-residue C-terminal fragment of TonB from Escherichia coli reveals significant conformational changes compared to structures of smaller TonB fragments. J. Biol. Chem. 280, 3022–3028 (2005).

    Article  Google Scholar 

  14. Peacock, R.S., Weljie, A.M., Howard, S.P., Price, F.D. & Vogel, H.J. The solution structure of the C-terminal domain of TonB and interaction studies with TonB box peptides. J. Mol. Biol. 345, 1185–1197 (2005).

    Article  CAS  Google Scholar 

  15. Sali, A. & Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).

    Article  CAS  Google Scholar 

  16. Laskowski, R.A., MacArthur, M.W. & Thornton, J.M. PROCHECK: a program to check the stereochemical quality of protein structure. J. Appl. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

  17. Kleywegt, G.J. Experimental assessment of differences between related protein crystal structures. Acta Crystallogr. D Biol. Crystallogr. 55, 1878–1884 (1999).

    Article  CAS  Google Scholar 

  18. Bell, P.E., Nau, C.D., Brown, J.T., Konisky, J. & Kadner, R.J. Genetic suppression demonstrates interaction of TonB protein with outer membrane transport proteins in Escherichia coli. J. Bacteriol. 172, 3826–3829 (1990).

    Article  CAS  Google Scholar 

  19. Cadieux, N. & Kadner, R.J. Site-directed disulfide bonding reveals an interaction site between energy-coupling protein TonB and BtuB, the outer membrane cobalamin transporter. Proc. Natl. Acad. Sci. USA 96, 10673–10678 (1999).

    Article  CAS  Google Scholar 

  20. Rosenblatt, D.S., Hosack, A., Matiaszuk, N.V., Cooper, B.A. & Laframboise, R. Defect in vitamin B12 release from lysosomes: newly described inborn error of vitamin B12 metabolism. Science 228, 1319–1321 (1985).

    Article  CAS  Google Scholar 

  21. Pezacka, E.H. & Rosenblatt, D.S. Intracellular metabolism of cobalamin. Altered activities of β-axial-ligand transferase and microsomal cob(III)alamin reductase in cblC and cblD fibroblasts in Advances in Thomas Addison's Diseases 315–323 (Journal of Endocrinology, Bristol, UK, 1994).

  22. Brudno, M. et al. LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA. Genome Res. 13, 721–731 (2003).

    Article  CAS  Google Scholar 

  23. Watkins, D. Cobalamin metabolism in methionine-dependent human tumour and leukemia cell lines. Clin. Invest. Med. 21, 151–158 (1998).

    CAS  PubMed  Google Scholar 

  24. Watkins, D., Matiaszuk, N. & Rosenblatt, D.S. Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH). J. Med. Genet. 37, 510–513 (2000).

    Article  CAS  Google Scholar 

  25. Ewing, B., Hillier, L., Wendl, M.C. & Green, P. Base-calling of automated sequencer traces using Phred I. Accuracy assesment. Genome Res. 8, 175–185 (1998).

    Article  CAS  Google Scholar 

  26. Gordon, D., Abajian, C. & Green, P. Consed: A graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).

    Article  CAS  Google Scholar 

  27. Miller, A.D. & Buttimore, C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol. Cell. Biol. 6, 2895–2902 (1986).

    Article  CAS  Google Scholar 

  28. Yao, J. & Shoubridge, E.A. Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome C oxidase deficiency. Hum. Mol. Genet. 8, 2541–2549 (1999).

    Article  CAS  Google Scholar 

  29. Horton, P. & Nakai, K. Better prediction of protein cellular localization sites with the k nearest neighbors classifier. Proc. Int. Conf. Intell. Syst. Mol. Biol. 5, 147–152 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montreal, H3G 1B1, Quebec, Canada

    Jordan P Lerner-Ellis, Jamie C Tirone, David Watkins, Chantal F Morel, T Mary Fujiwara, Emily Moras, Hana Antonicka, Daniel Leclerc, Eric A Shoubridge, Kenneth Morgan & David S Rosenblatt

  2. Division of Medical Genetics, McGill University Health Centre, Montreal, H3G 1A4, Quebec, Canada

    Jordan P Lerner-Ellis, Jamie C Tirone, David Watkins, Chantal F Morel, T Mary Fujiwara, Emily Moras, Angela R Hosack, Gail V Dunbar, Daniel Leclerc, Kenneth Morgan & David S Rosenblatt

  3. Department of Microbiology and Immunology, McGill University, Montreal, H3A 2B4, Quebec, Canada

    Peter D Pawelek & James W Coulton

  4. McGill University and Genome Quebec Innovation Centre, Montreal, H3A 1A4, Quebec, Canada

    Carole Doré, Vince Forgetta & Pierre Lepage

  5. Department of Molecular and Medical Genetics, University of Toronto and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, M5G 1X8, Ontario, Canada

    Janet L Atkinson & Johanna M Rommens

  6. Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, Quebec, Canada

    Hana Antonicka & Eric A Shoubridge

  7. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, T2N 4N1, Alberta, Canada

    C Melissa Dobson & Roy A Gravel

Authors
  1. Jordan P Lerner-Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jamie C Tirone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter D Pawelek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carole Doré
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janet L Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Watkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chantal F Morel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Mary Fujiwara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Emily Moras
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Angela R Hosack
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gail V Dunbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hana Antonicka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Vince Forgetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. C Melissa Dobson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Daniel Leclerc
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Roy A Gravel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Eric A Shoubridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. James W Coulton
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Pierre Lepage
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Johanna M Rommens
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kenneth Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. David S Rosenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David S Rosenblatt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/ng1683

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1683

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing