Transcobalamin I (TC I) deficiency, a common cause of falsely low serum cobalamin (Cbl), is usually genetic, and plasma corrinoid analogs are decreased: is “withholding” Cbl and its analogs from human cells and the microbiome the chief biological role for TC I?

TC I is the most ubiquitous and abundant human Cbl‐binding protein but differs by not promoting Cbl uptake by cells. It carries all nonfunctional corrinoid analogs and >;70% of Cbl in plasma. Once thought rare, mild TC I deficiency (mTC I def) may cause 15% of low Cbl levels, which led us to examine TC I def and its implications for TC I biology. mTC I def and severe TC I def (sTC I def) were identified by TC I immunoassay. Plasma analogs were estimated by differential results between radioisotope dilution Cbl assays using TC I or intrinsic factor as binding proteins. All 4 studied patients with sTC I def were non‐Caucasian and homozygous or compound heterozygous for nonsense and deleterious missense TCN1 mutations (270delG; 315C>;T; 475T>;C). In mTC I def, 21 non‐Caucasian patients and affected relatives (14 families) were heterozygous for 270delG and 1 for 315C>;T, and 12 Caucasian patients (9 families) for 999G>;T, a deleterious missense mutation. Only 18 unrelated families with mTC I def had no detectable mutations. Analogs were decreased nonsignificantly in mTC I def plasma and absent in sTC I def. The TCN1 mutations in 24 of 42 families (57%) suggest that mTC I def is usually hereditary. We propose that the chief function of TC I is to withhold both Cbl and analogs from a variety of cells for a variety of reasons. The frequency of ethnically specific mutations suggests possible selective pressures to modulate TC I in diverse populations.