UTP4 – Hereditary North American Indian Childhood Cirrhosis

This summary evaluates the association between UTP4 and hereditary North American Indian childhood cirrhosis, a severe autosomal recessive intrahepatic cholestasis seen predominantly in Ojibway-Cree children. Multiple independent studies have identified a recurrent founder missense allele, supporting its relevance in the pathogenesis of the disease (PMID:12417987).

The clinical validity of this association is rated as Strong according to ClinGen criteria. A key case report identified the recurrent c.1693C>T (p.Arg565Trp) variant in a proband, and additional multi‑patient studies have reinforced this finding with clear evidence of segregation in affected families and concordant clinical features (PMID:12417987).

Genetic evidence is robust: the pathogenic missense variant c.1693C>T (p.Arg565Trp) was observed in independent cases and displays autosomal recessive inheritance. The variant has been detected in all affected NAIC chromosomes and is supported by segregation analyses demonstrating its recurrence in multiple affected individuals (PMID:12417987).

Functional studies have provided moderate but compelling support for this gene disease association. In vitro assays have demonstrated that the p.Arg565Trp substitution impairs critical protein interactions, while zebrafish models have shown that knockdown of the UTP4 homolog disrupts biliary development and recapitulates the human cholestatic phenotype. These findings from cellular and animal models are consistent with a pathogenic mechanism impacting ribosome biogenesis and cellular stress pathways (PMID:19732766, PMID:24147052).

Although no significant conflicting evidence has been reported, the current dataset integrates well-established genetic and functional findings to support the strong association between UTP4 and NAIC. The absence of studies disputing these results further reinforces the clinical relevance of the c.1693C>T (p.Arg565Trp) variant.

In summary, the convergence of genetic data from case and multi‑patient studies with supportive functional evidence underscores a strong association between UTP4 and hereditary North American Indian childhood cirrhosis. This integrated assessment provides a reliable basis for diagnostic decision‑making, commercial applications, and future publication.

Key Take‑home Message: The recurrent c.1693C>T (p.Arg565Trp) variant in UTP4 is strongly implicated in NAIC, supported by consistent genetic segregation and functional deficits, making it a critical target for clinical interpretation.

References

• American journal of human genetics • 2002 • A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. PMID:12417987
• Annals of medicine • 2004 • Molecular basis of intrahepatic cholestasis. PMID:15768832
• Experimental cell research • 2009 • Cirhin up‑regulates a canonical NF‑kappaB element through strong interaction with Cirip/HIVEP1. PMID:19732766
• PloS one • 2013 • p53‑mediated biliary defects caused by knockdown of cirh1a, the zebrafish homolog of the gene responsible for North American Indian Childhood Cirrhosis. PMID:24147052

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