Transcobalamin deficiency due to activation of an intra exonic cryptic splice site

• Published in: British journal of haematology Vol. 123; no. 5; pp. 915 - 920
• Main Authors: Namour, Fares, Helfer, Anne‐Catherine, Quadros, Edward V., Alberto, Jean‐Marc, Bibi, Ha M., Orning, Lars, Rosenblatt, David S., Jean‐Louis, Guéant
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.12.2003; Blackwell; Blackwell Publishing Ltd
• Subjects: Adult; anaemia; Anemia, Megaloblastic - blood; Anemia, Megaloblastic - genetics; Anemias. Hemoglobinopathies; Animals; Biological and medical sciences; Child; COS Cells - metabolism; Diseases of red blood cells; Electrophoresis, Polyacrylamide Gel; Female; Genotype; Hematologic and hematopoietic diseases; Hematology; Humans; Male; Medical sciences; mutation; Parents; Point Mutation; Reverse Transcriptase Polymerase Chain Reaction; RNA Splice Sites; Siblings; splice site; transcobalamin deficiency; Transcobalamins - analysis; Transcobalamins - deficiency; Transcobalamins - genetics; Transfection; Vitamin B 12 - metabolism; vitamin B12; Human; anaemia; Anemia; Deficiency; transcobalamin deficiency; Clinical form; Hemopathy; Case study; Gene; splice site; Genetics; Complication; Female; vitamin B12; Mutation; Child
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.2003.04685.x

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.