title: Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.
abstract: Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B(12) (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood. The cblC locus was mapped to chromosome region 1p by linkage analysis. 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.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada, H3G 1B1.
authors.forename: Jordan P
authors.initials: JP
authors.lastname: Lerner-Ellis
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Tirone
authors.forename: Peter D
authors.initials: PD
authors.lastname: Pawelek
authors.forename: Carole
authors.initials: C
authors.lastname: Doré
authors.forename: Janet L
authors.initials: JL
authors.lastname: Atkinson
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: Chantal F
authors.initials: CF
authors.lastname: Morel
authors.forename: T Mary
authors.initials: TM
authors.lastname: Fujiwara
authors.forename: Emily
authors.initials: E
authors.lastname: Moras
authors.forename: Angela R
authors.initials: AR
authors.lastname: Hosack
authors.forename: Gail V
authors.initials: GV
authors.lastname: Dunbar
authors.forename: Hana
authors.initials: H
authors.lastname: Antonicka
authors.forename: Vince
authors.initials: V
authors.lastname: Forgetta
authors.forename: C Melissa
authors.initials: CM
authors.lastname: Dobson
authors.forename: Daniel
authors.initials: D
authors.lastname: Leclerc
authors.forename: Roy A
authors.initials: RA
authors.lastname: Gravel
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
authors.forename: James W
authors.initials: JW
authors.lastname: Coulton
authors.forename: Pierre
authors.initials: P
authors.lastname: Lepage
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.forename: Kenneth
authors.initials: K
authors.lastname: Morgan
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002874:Chromosome Mapping; D017124:Conserved Sequence; D005347:Fibroblasts / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006712:Homocystinuria / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry; D008661:Metabolism, Inborn Errors / Q000235:genetics*; D008764:Methylmalonic Acid / Q000652:urine*; D008969:Molecular Sequence Data; D009154:Mutation; D010088:Oxidoreductases; D017510:Protein Folding; D040681:Structural Homology, Protein; D014805:Vitamin B 12 / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; C057616:tonB protein, Bacteria; D008764:Methylmalonic Acid; C508359:MMACHC protein, human; D010088:Oxidoreductases; D014805:Vitamin B 12