title: Lessons in biology from patients with inherited disorders of vitamin B12 and folate metabolism.
abstract: BACKGROUND
  Over the last forty years, our laboratory has accumulated a collection of over 1000 cultured fibroblast lines derived from patients from around the world referred with signs of inborn errors of cobalamin or folate metabolism, including several hundred with complementation-confirmed diagnoses. By accurately classifying patient disorders into classes representing blocks affecting specific reactions, we have provide the basis for rational assessment of phenotypic heterogeneity, and development of methods for diagnosis, treatment and prognosis. These resources have been valuable in identification of causal genes for known inborn errors. Since 2000, we and our collaborators identified the genes for the cblA (MMAA), cblB (MMAB), cblC (MMACHC), cblD (MMADHC), and cblF (LMBRD1) disorders.
  
  
  RESULTS
  Whole exome sequencing of DNA from a patient with severe combined immunodeficiency (SCID), megaloblastic anemia and hemolytic uremic syndrome identified mutations in the MTHFD1 gene, which encodes a trifunctional enzyme involved in interconversion of folate coenzyme derivatives. This disorder demonstrates the importance de novo pyrimidine synthesis in the etiology of SCID. Mutations in the ABCD4 gene have been identified in four patients with accumulation of unbound cobalamin in lysosomes; this gene encodes a lysosomal membrane protein that plays a role in the transport of cobalamin across this membrane. Mutations in the HCFC1 gene on the X chromosome have been identified in several male patients that had received a diagnosis of cblC on the basis of complementation studies in cultured fibroblasts. HCFC1 encodes a transcription factor that regulates expression of a number of genes, including MMACHC, the gene that is mutated in patients with the cblC disorder. These studies demonstrate that with the advent of affordable whole exome sequencing, it has been possible to identify genes for novel inborn errors of cobalamin metabolism, often working from a small number of affected patients.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada. Electronic address: david.rosenblatt@mcgill.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000749:Anemia, Megaloblastic / Q000235:genetics / Q000378:metabolism*; D059472:Exome; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000378:metabolism*; D051863:Host Cell Factor C1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics / Q000378:metabolism; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000378:metabolism*; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism*
chemical_list: C489273:ABCD4 protein, human; D018528:ATP-Binding Cassette Transporters; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D015778:Minor Histocompatibility Antigens; D005492:Folic Acid; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D050721:Proto-Oncogene Proteins c-cbl; C119570:CBLC protein, human; D014805:Vitamin B 12
keywords: Cobalamin; Exome sequencing; Folate; Immunodeficiency; SCID; Vitamin B(12)