Genetic patterns of transcobalamin II and the relationships with congenital defects

Abstract

The vitamin B12-binding protein, transcobalamin II, is a trace component of plasma with a rapid turnover. This protein is essential for absorption, transport, cellular uptake and for recycling of vitamin B12 (cobalamin). Congenital transcobalamin II deficiency, an inborn error of metabolism is inherited as a recessive trait. The homozygous form of the deficiency is accompanied by severe clinical, hematological and immunological disturbances in the first months of life. Analytical, genetic, biochemical and clinical aspects of transcobalamin II in man and in vertebrates have been reviewed here. A genetic polymorphism for the protein has been found in man, rabbits and mice. Family studies revealed that the genetic patterns in man are determined by four polymorphic and several rare alleles. This genetic variability has been applied in paternity testing and in population studies. Transcobalamin II typing in families of patients with the inherited functional deficiency has led to identification of various deficient alleles in heterozygous carriers of the defects. Applying transcobalamin II typing after bone marrow transplantation demonstrated that this protein originates partly in the bone marrow. Subsequent investigations in cell culture have shown that human skin fibroblasts and cultured bone marrow synthesize and secret isotypes of a transport protein corresponding to the genetic isotypes observed in plasma. Comparison of transcobalamin II types in umbilical cord serum with the maternal types, has proven that the transcobalamin II activity in the cord serum is derived from the fetus. This finding will be of crucial importance in the early diagnosis of the deficiency syndrome.

Transcobalamin II deficiency: Case report and review of the literature

“…Cobalamin is taken up by cells only when bound to TCII [8]. The rest of extracellular cobalamin is bound to a group of a-glycoproteins with a high affinity for cobalamin; these are electrophoretically rapid and are called "R-binders" and include transcobalamin I and transcobalamin III [6,8,14]. Their function is not known but it has been suggested that they may act as a transport system to remove noxious cobalamin analogues from the brain and other tissues [15].…”

“…This suggests that the patient is homozygous for an abnormal gene responsible for the lack of B~2 binding capacity and low or undetectable immunoreactive TCII levels. This more common phenotype detected by electrophoresis was first described in a family from Seattle [6]. The patient was commenced on 200 gg of cyanocobalamin i.m.…”

“…The gene for TCII has recently been identified on chromosome 22 [2]. Genetic polymorphism for the protein has been described [6], but the clinical features of TCII deficiency have been similar in most of the reported cases. As more cases are described and investigated, new facets of this entity are beginning to reveal the genetic heterogeneity of this disorder.…”

TC II deficiency: avoidance of false-negative molecular genetics by RNA-based investigations

“…Serum Cbl levels cannot serve as a diagnostic tool because they show as normal and most of serum Cbl is bound to haptocorrin (or R-binder, formerly named transcobalamin I), a glycoprotein whose function is not fully understood. 4,5 In this study, the genetic work-up of two patients with typical earlyonset TC II deficiency is reported. Exon amplification and sequencing of the TCII gene was uninformative with regard to the definite genetic background in both patients.…”

“…Symptoms include megaloblastic anemia and pancytopenia, vomiting, diarrhea and early-onset of failure to thrive, repeated infections, and mental retardation. [4][5][6][7][8] The disorder is inherited in an autosomal-recessive trait and was first described in 1971 in two siblings with megaloblastic anemia and normal levels of serum Cbl. 9 Diagnosis can either be achieved by the measurement of serum transcobalamin by an enzyme-linked immunosorbent assay method 10 or by genetic testing.…”