Genomic mutations associated with mild and severe deficiencies of transcobalamin I (haptocorrin) that cause mildly and severely low serum cobalamin levels

Abstract

Summary 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.

Laboratory Evaluation for Vitamin B12 Deficiency: The Case for Cascade Testing

“…18 More work needs to be done to sort out the genetics and pathophysiology related to cobalamin deficiency. 19 Some, but not all, studies have found marginally better performance (as assessed by receiver operator curves) by holoTC when compared with serum B 12 .…”

Low cobalamin levels associated with sickle cell disease: Contrasting origins and clinical meanings in two instructive patients

“…Both the TC I and ß-globin genes are located on chromosome 11, but linkage dysequilibrium is unlikely because their locations are far apart (11q12-13 and 11p15, respectively) and their mutation dosages do not match in many cases (Table II). Pending clarification of TC I function and organization of large prospective surveys applying appropriate assays17 and genetic tools,24,31 the association between TC I deficiency and sickle cell disease may turn out to be indirect, perhaps involving an unidentified selection pressure.…”

Subclinical cobalamin deficiency

“…]. Homozygosity and compound heterozygosity cause absence of transcobalamin I, thereby inducing cobalamin levels less than 100 ng/l; these are typically misdiagnosed and treated as cobalamin deficiency [19]. Simple heterozygosity decreases transcobalamin I and cobalamin modestly and mimics SCCD [18-21,22 & ].…”