title: False low holotranscobalamin levels in a patient with a novel TCN2 mutation.
abstract: BACKGROUND
  Measurement of holotranscobalamin (holoTC) is increasingly used as a screening test for cobalamin (Cbl) deficiency. A level well below the reference interval strongly supports a deficient state. We examined a 21-year-old woman diagnosed as Cbl deficient because of an extremely low holoTC level as measured by the Abbott Architect Assay.
  
  
  METHODS
  The patient was evaluated for Cbl deficiency employing an in-house holoTC method as well as other routine markers of Cbl status. Further analyses included exploration of the Cbl binding proteins employing gel filtration of a serum sample saturated with 57 Co-labeled Cbl and Sanger sequencing of exons 1-9 and the intron-exon boundaries of the TCN2 gene, the gene coding for transcobalamin (TC).
  
  
  RESULTS
  The patient had normal hematological variables throughout. Despite initial treatment with Cbl, holoTC as measured by the Abbott assay remained low, while holoTC measured with the in-house assay was normal, and behaved as TC upon gel-filtration. By Sanger sequencing, we detected a homozygous single point mutation c.855T>A in exon 6 of TCN2, corresponding to a asparagine (Asn) to lysine (Lys) substitution in position 267 of the mature protein.
  
  
  CONCLUSIONS
  We describe a novel point mutation of the TCN2 gene. The mutation does not seem to interfere with the function of TC, but the mutation may well explain the low level of holoTC detected by the Abbott assay. Our results underscores that mutations of TCN2 have to be considered when implausible holoTC results are obtained.
authors.forename: Peter
authors.initials: P
authors.lastname: Keller
authors.forename: Janine
authors.initials: J
authors.lastname: Rufener
authors.forename: Christof
authors.initials: C
authors.lastname: Schild
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Fedosov
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nissen
authors.forename: Ebba
authors.initials: E
authors.lastname: Nexo
mesh_terms: D000328:Adult; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D017354:Point Mutation; D014155:Transcobalamins / Q000235:genetics*; D014805:Vitamin B 12 / Q000097:blood*; D055815:Young Adult
chemical_list: D014155:Transcobalamins; D014805:Vitamin B 12