title: Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels.
abstract: Transcobalamin (TC) I deficiency, like the function of TC I itself, is incompletely understood. It produces low serum cobalamin levels indistinguishable from those of true cobalamin deficiency. Diagnosis is especially elusive when TC I deficiency is mild. To provide new, more substantive definition, the TCN1 gene was examined in two well-characterised families that included members with both severe and mild TC I deficiencies. A severely deficient proposita with undetectable TC I levels displayed compound heterozygosity for two mutations, each causing a premature stop codon. Relatives in both families who had mildly low or low-normal plasma levels of TC I and cobalamin were heterozygous for one or the other of these mutations. An unrelated patient with mild TC I deficiency and unknown familial TC I and cobalamin status was then tested and found to be similarly heterozygous for one of the mutations. The two nonprivate mutations identify a genetic basis for TC I deficiency for the first time. They also add new approaches to studying mild and severe TC I deficiency and to reducing confusion of its low cobalamin levels with those of cobalamin deficiency and its often dramatically different prognosis and management.
authors.affiliation: Department of Medicine, New York Methodist Hospital, Brooklyn, NY 11215, USA. rac9001@nyp.org
authors.forename: Ralph
authors.initials: R
authors.lastname: Carmel
authors.forename: James
authors.initials: J
authors.lastname: Parker
authors.forename: Zvi
authors.initials: Z
authors.lastname: Kelman
mesh_terms: D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D014155:Transcobalamins / Q000032:analysis / Q000172:deficiency* / Q000235:genetics; D014805:Vitamin B 12 / Q000097:blood*; D014806:Vitamin B 12 Deficiency / Q000175:diagnosis
chemical_list: D014155:Transcobalamins; D014805:Vitamin B 12