TCN2 – Transcobalamin II deficiency

Transcobalamin II (TCN2) deficiency is a rare autosomal recessive disorder of cobalamin transport caused by biallelic loss-of-function variants in TCN2. Affected infants typically present in early infancy with failure to thrive, megaloblastic anemia, pancytopenia, immunodeficiency and neurological features responsive to parenteral hydroxocobalamin.

Genetic evidence includes over 20 unrelated probands harboring homozygous or compound heterozygous loss-of-function alleles across multiple cohorts (PMID:7980584, PMID:7849710, PMID:19581117, PMID:20607612, PMID:23430814, PMID:33023511). A recurrent frameshift, c.1031_1032del (p.Arg344ThrfsTer20), was identified in a Chinese pedigree and correlates with absent TCN2 protein and complete loss of plasma TC activity (PMID:36035190).

Segregation in affected families includes two siblings with compound heterozygous splicing and frameshift alleles, confirming autosomal recessive inheritance (PMID:20607612). Case series of seven unrelated patients and fibroblast cDNA analyses further demonstrate consistent genotype–phenotype correlations.

Functional studies using patient-derived fibroblasts and lymphocytes show TCN2 mRNA decay and absent protein expression, leading to defective cellular uptake of cobalamin and intracellular methylmalonic acid accumulation (PMID:7849710, PMID:20607612). In silico domain analyses and bioinformatic modeling support disruption of the cobalamin-binding domain in missense variants.

No significant conflicting evidence has been reported; all studies uniformly support a loss-of-function mechanism. The breadth of pathogenic alleles, segregation data, and concordant functional assays meet criteria for a Definitive gene–disease relationship.

Key take-home: Early genetic testing for TCN2 variants enables prompt parenteral hydroxocobalamin therapy, preventing irreversible hematologic and neurologic sequelae in transcobalamin II deficiency.

References

• Biochemical and biophysical research communications • 1994 • Nonsense mutations in human transcobalamin II deficiency. PMID:7980584
• Human molecular genetics • 1994 • Identification of two mutant alleles of transcobalamin II in an affected family. PMID:7849710
• Molecular genetics and metabolism • 2009 • Transcobalamin II deficiency at birth. PMID:19581117
• Journal of inherited metabolic disease • 2010 • Transcobalamin deficiency caused by compound heterozygosity for two novel mutations in the TCN2 gene: a study of two affected siblings, their brother, and their parents. PMID:20607612
• JIMD reports • 2013 • Expanding the Spectrum of Methylmalonic Acid-Induced Pallidal Stroke: First Reported Case of Metabolic Globus Pallidus Stroke in Transcobalamin II Deficiency. PMID:23430814
• BMC pediatrics • 2020 • Identification of transcobalamin deficiency with two novel mutations in the TCN2 gene in a Chinese girl with abnormal immunity: a case report. PMID:33023511
• Frontiers in genetics • 2022 • Case report: Novel compound-heterozygous mutations in the TCN2 gene identified in a chinese girl with transcobalamin deficiency. PMID:36035190

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