UROC1 – Urocanic Aciduria

UROC1 encodes urocanase, an enzyme in histidine catabolism; pathogenic biallelic variants have been detected in three individuals from two families with biochemical accumulation of urocanic acid, consistent with autosomal recessive inheritance (PMID:30619714, PMID:19304569). Two phenotypically normal siblings harbor compound heterozygous variants in UROC1 with marked urocanase deficiency but without clinical sequelae (PMID:30619714), while a separate case exhibited intellectual disability and intermittent ataxia associated with the c.1348C>T (p.Arg450Cys) variant (PMID:19304569). Genetic evidence comprises three affected individuals across two families with limited segregation (one additional sibling) and variant classes including missense changes c.209T>C (p.Leu70Pro) and c.1348C>T (p.Arg450Cys). Functional assays have demonstrated in silico disruption of structural elements, reduced protein expression, and negligible enzyme activity for both substitutions, supporting a loss-of-function mechanism (PMID:19304569). However, the presence of a benign biochemical phenotype in affected siblings without clinical manifestations argues against a primary disease-causing role for UROC1 variants in urocanic aciduria. Collectively, these data result in a disputed gene–disease association due to conflicting clinical outcomes and limited segregation. Key Take-home: UROC1 variant detection may confirm biochemical urocanase deficiency but lacks consistent clinical correlates, underscoring the need for comprehensive evaluation of developmental symptoms.

References

• Molecular genetics and metabolism reports | 2019 | Untargeted metabolomics identifies unique though benign biochemical changes in patients with pathogenic variants in UROC1. PMID:30619714
• Journal of medical genetics | 2009 | Mutations in the urocanase gene UROC1 are associated with urocanic aciduria. PMID:19304569

Evidence Based Scoring (AI generated)