UROC1 was first reported in relation to autosomal recessive urocanic aciduria in 2009 (Espinos et al., PMID: 19304569), although association of the biochemical abnormality with the protein urocanase was characterized in 1971 (Yoshida et al., PMID: 5124677). There have been a variety of phenotypes reported in association with urocanic aciduria, including intellectual disability and developmental delay, however the relationship of these phenotypes to the biochemical abnormality is unclear. Four unique missense variants and one nonsense varaint have been reported in humans thus far. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in four probands in four separate publications (PMIDs: 19304569, 30619714, 32439973, 27391121). One family was asymptomatic except for the characteristic urocanic aciduria (PMID: 30619714). Segregation was observed and confirmed in one sibling in this family. The mechanism for disease is biallelic loss of function, with loss of enzyme activity resulting in a buildup of the prior metabolite in the histidine metabolic pathway, urocanic acid. This gene-disease association is additionally supported by unique expression in the human liver, correlating with the proposed pathogenic mechanism, and by the protein's function correlating with the resulting biochemical abnormality. However, the lack of any relevant animal models or functional data limits the conclusiveness of this evidence. In summary, there is Moderate evidence to support this gene-disease relationship. Although more evidence, particularly observation in human probands and functional data, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
This classification was originally approved by the Aminoacidopathy Gene Curation Expert Panel on November 13, 2020. This gene-disease relationship was re-evaluated on March 7, 2024. Two new patients with the NM_144639.3(UROC1):c.855G>A (p.Trp285Ter) variant were added (PMIDs: 32439973, 27391121). As a result of this re-evaluation, the classification increased from Limited to Moderate.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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