Lessons in biology from patients with inherited disorders of vitamin B12 and folate metabolism

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.