NT5C3A – Pyrimidine 5′-Nucleotidase Deficiency

NT5C3A encodes the cytosolic pyrimidine 5′-nucleotidase type I enzyme (P5'N-1). Loss-of-function variants in NT5C3A cause autosomal recessive nonspherocytic hemolytic anemia due to pyrimidine 5′-nucleotidase deficiency ([MONDO:0009946]). Affected individuals present with macrocytic anemia, pronounced basophilic stippling, and accumulation of pyrimidine nucleotides in erythrocytes. Early genetic studies identified three homozygous mutations in separate kindreds, defining the gene structure and location on chromosome 7 ([PMID:11369620]). Subsequent cohort analyses have expanded the mutation spectrum and confirmed the clinical phenotype.

P5N deficiency follows an autosomal recessive inheritance pattern, with both alleles affected in patients. Screening of 11 unrelated families revealed seven distinct pathogenic mutations, including missense, splice-site, and nonsense variants ([PMID:12930399]). Additional population studies described six unrelated Italian patients carrying four novel mutations, some showing geographic clustering in southern Italy ([PMID:12930399]). A recent case report described a 65-year-old female with a homozygous c.693+1G>A splice-site change linking molecular diagnosis to clinical presentation ([PMID:39967523]). Overall, at least 14 probands have been molecularly confirmed, supporting a robust genetic basis.

Segregation data are limited but supportive of pathogenicity. A South American father–daughter pair with homozygous p.Arg56Gly demonstrated co-segregation of disease alleles within one family ([PMID:25153905]). Parental consanguinity in select pedigrees further underscores the recessive inheritance.

Functional assays on recombinant P5'N-1 variants consistently reveal impaired catalytic efficiency and reduced thermostability. Four missense mutants (p.Asp87Val, p.Leu131Pro, p.Asn179Ser, p.Gly230Arg) showed markedly decreased UMP/CMP hydrolysis and heat sensitivity ([PMID:15604219]). Additional variants (p.Cys63Arg, p.Gly157Arg, p.Ile247Thr) exhibited similar losses of enzyme activity and stability, providing a mechanistic rationale for erythrocyte dysfunction ([PMID:18499901]).

No conflicting evidence has emerged; all reported variants are absent from population controls and correlate with enzymatic defects. Although residual P5'N-1 activity varies among alleles, clinical severity is not strictly predicted by residual enzyme levels, suggesting compensatory metabolic pathways.

References

• British journal of haematology • 2003 • Molecular characterization of six unrelated Italian patients affected by pyrimidine 5'-nucleotidase deficiency. PMID:12930399
• Blood • 2005 • Functional analysis of pyrimidine 5'-nucleotidase mutants causing nonspherocytic hemolytic anemia. PMID:15604219
• Blood cells, molecules & diseases • 2008 • Molecular basis of pyrimidine 5'-nucleotidase deficiency caused by 3 newly identified missense mutations (c.187T>C, c.469G>C and c.740T>C) and a tabulation of known mutations. PMID:18499901
• Haematologica • 2014 • Pyrimidine-5'-nucleotidase Campinas, a new mutation (p.R56G) in the NT5C3 gene associated with pyrimidine-5'-nucleotidase type I deficiency and influence of Gilbert's Syndrome on clinical expression. PMID:25153905
• Clinical laboratory • 2025 • Pyrimidine-5'-Nucleotidase Deficiency: a New Homozygous NT5C3A Mutation (c.693+1G>A variant). PMID:39967523
• Blood • 2001 • Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency. PMID:11369620

Evidence Based Scoring (AI generated)