Transcobalamin deficiency due to activation of an intra exonic cryptic splice site.
Transcobalamin (TC), a vitamin B12 (cobalamin, Cbl) binding protein in plasma, promotes the cellular uptake of the vitamin by receptor-mediated endocytosis. Inherited TC deficiency is an autosomal recessive disorder characterized by megaloblastic anaemia caused by cellular vitamin B12 depletion. It may be accompanied by neurological complications, including a delay in psychomotor and mental development. This report describes three sisters with inherited TC deficiency resulting from a splicing defect in the TC gene. A point mutation was identified in intron 3 splice site of the TC gene that activates a cryptic splice site in exon 3. The transcript generated has an in-frame deletion of 81 nucleotides and the resulting truncated protein is unstable and not secreted by the cells. Until now, genetic studies have been reported in only five patients with TC deficiency and the molecular defect was different in each of them, which gives evidence for a genetic heterogeneity of the disease.
Namour
Fares
F
Laboratoire de Pathologie Cellulaire et Moléculaire en Nutrition, EMI-INSERM 0014, Faculté de Médecine de Nancy, Cedex, France. b.namour@chu-nancy.fr
Helfer
Anne-Catherine
AC
Quadros
Edward V
EV
Alberto
Jean-Marc
JM
Bibi
Ha M
HM
Orning
Lars
L
Rosenblatt
David S
DS
Jean-Louis
Guéant
G
D000328:Adult; D000749:Anemia, Megaloblastic / Q000097:blood / Q000235:genetics*; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D002648:Child; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010290:Parents; D017354:Point Mutation; D022821:RNA Splice Sites; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035781:Siblings; D014155:Transcobalamins / Q000032:analysis / Q000172:deficiency* / Q000235:genetics*; D014162:Transfection; D014805:Vitamin B 12 / Q000378:metabolism
D022821:RNA Splice Sites; D014155:Transcobalamins; D014805:Vitamin B 12