Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.
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.
Lerner-Ellis
Jordan P
JP
Department of Human Genetics, McGill University, Montreal, Quebec, Canada, H3G 1B1.
Tirone
Jamie C
JC
Pawelek
Peter D
PD
Doré
Carole
C
Atkinson
Janet L
JL
Watkins
David
D
Morel
Chantal F
CF
Fujiwara
T Mary
TM
Moras
Emily
E
Hosack
Angela R
AR
Dunbar
Gail V
GV
Antonicka
Hana
H
Forgetta
Vince
V
Dobson
C Melissa
CM
Leclerc
Daniel
D
Gravel
Roy A
RA
Shoubridge
Eric A
EA
Coulton
James W
JW
Lepage
Pierre
P
Rommens
Johanna M
JM
Morgan
Kenneth
K
Rosenblatt
David S
DS
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
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