The Transcobalamin (TC) Codon 259 Genetic Polymorphism Influences Holo-TC Concentration in Cerebrospinal Fluid from Patients with Alzheimer Disease
Henrik Zetterberg1,a, Ebba Nexö2, Björn Regland3, Lennart Minthon4, Roberta Boson4, Mona Palmér1, Lars Rymo1 and Kaj Blennow1,
1 Department of Clinical Chemistry and Transfusion Medicine,

Two proteins bind vitamin B12 in plasma: haptocorrin (transcobalamin I) and transcobalamin (transcobalamin II; TC). The latter is the critical transporter that delivers vitamin B12 to peripheral tissues. TC carries one-third of the circulating B12 (holo-TC), but most TC is unsaturated (apo-TC) Polyacrylamide gel electrophoresis has revealed two common TC isotypes, M and X, and two rare variants, S and F that may influence the cellular availability of vitamin B12 The phenotypic variability is a multifactorial phenomenon that probably includes cell-type-specific processing of translated TC but the substitution of proline (P) for arginine (R) at codon 259 of the TC gene is the major determinant of the TC variability, at least in Caucasians, and affects TC concentrations in plasma Most 259PP individuals have the TC M phenotype, whereas most 259RR individuals have the X phenotype.

In agreement with previously published studies, we found no associations between the TC P259R polymorphism and concentrations of tHcy, vitamin B12, or folate, but we did find a significant relationship of the polymorphism with total TC in plasma. The lower concentrations of total TC in both plasma and CSF in 259PR and 259RR individuals suggest that the 259R allele impairs TC expression, stability, and/or metabolism. We were, however, unable to confirm the previously reported association between the 259R allele and lower concentrations of holo-TC in plasma. Nevertheless, holo-TC in CSF was reduced in patients with the 259PR and 259RR genotypes, showing that the polymorphism indeed affected holo-TC concentrations in CNS. Holo-TC concentrations in plasma and CSF were highly correlated, which is compatible with the notion that all holo-TC in CSF originates from plasma and needs to pass the blood–brain barrier to enter the CNS.…….(report truncated). 

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