UPB1 – Beta-ureidopropionase deficiency

Beta-ureidopropionase deficiency is an autosomal recessive inborn error of pyrimidine degradation caused by biallelic variants in UPB1 and is clinically designated as beta-ureidopropionase deficiency. Affected individuals accumulate N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid, detectable by GC-MS or NMR.

In an initial report of four unrelated individuals, compound heterozygous splice-site mutations c.105-2A>G and c.917-1G>A and a missense change c.254C>A (p.Ala85Glu) abolished enzyme activity in liver biopsy and recombinant assays (PMID:15385443). A fifth proband presented with urogenital and colorectal anomalies harboring c.209G>C (p.Arg70Pro) and c.105-2A>G, with complete loss of residual activity in expression studies (PMID:17964839).

Subsequent case series have documented approximately 30 genetically confirmed patients, including an 11-month-old with homozygous c.977G>A (p.Arg326Gln) — a variant with an allele frequency of 1.7% in East Asians (PMID:25445412). However, homozygous p.Arg326Gln individuals are often asymptomatic, and population databases report carrier frequencies incompatible with a fully penetrant rare disorder (PMID:35926322).

Functional assessments in Escherichia coli and mammalian cells demonstrate that missense variants such as p.Ala85Glu, p.Arg70Pro, p.Gly31Ser, p.Thr129Met, p.Ser300Leu, and p.Asn345Ile result in absent or severely reduced β-ureidopropionase activity. Structural modelling indicates active-site disruption or impaired oligomer assembly (PMID:22525402; PMID:35151535).

Despite consistent loss-of-function data, the high prevalence of key variants (notably p.Arg326Gln) and the presence of asymptomatic homozygotes challenge direct genotype-phenotype correlations. Current evidence supports a Disputed gene–disease assignment due to uncertain clinical penetrance and variable expressivity.

Key Take-home: UPB1 variant analysis should be interpreted alongside biochemical assays; routine inclusion in carrier or diagnostic panels remains premature.

References

• Human molecular genetics • 2004 • beta-Ureidopropionase deficiency: an inborn error of pyrimidine degradation associated with neurological abnormalities. PMID:15385443
• Molecular genetics and metabolism • 2008 • Beta-ureidopropionase deficiency presenting with congenital anomalies of the urogenital and colorectal systems. PMID:17964839
• Clinica chimica acta; international journal of clinical chemistry • 2015 • NMR-based urinalysis for rapid diagnosis of β-ureidopropionase deficiency in a patient with Dravet syndrome PMID:25445412
• Molecular genetics and metabolism • 2022 • The relationship between beta-ureidopropionase deficiency due to UPB1 variants and human phenotypes is uncertain. PMID:35926322
• Biochimica et biophysica acta • 2012 • β-ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients PMID:22525402
• Molecular genetics and metabolism • 2022 • β-Ureidopropionase deficiency due to novel and rare UPB1 mutations affecting pre-mRNA splicing and protein structural integrity and catalytic activity PMID:35151535

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