VIPAS39 – Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder characterized by congenital joint contractures, cholestasis, renal tubular dysfunction, ichthyosis, and severe failure to thrive. Biallelic variants in VIPAS39 (encoding the protein VPS16B) have emerged as a distinct genetic cause of ARC, highlighting genetic heterogeneity alongside VPS33B mutations.

VIPAS39 encodes an adaptor for the homotypic fusion and protein sorting (HOPS) complex, crucial for apical-basolateral polarity and endosomal maturation in hepatocytes and renal epithelial cells. Disruption of VIPAS39 perturbs epithelial tight junction formation and protein sorting, mechanistically linking to the multisystem ARC phenotype.

To date, at least 10 probands from three unrelated kindreds harbor biallelic VIPAS39 variants (PMID:39736737). Segregation was confirmed in a sibling pair (PMID:39736737). Reported alleles include truncating mutations (e.g., c.643C>T (p.Arg215Ter)) and splice-site defects, consistent with a loss-of-function mechanism.

The variant spectrum in VIPAS39 comprises five truncating and one canonical splice-site variant (PMID:39736737). Population data indicate these alleles are extremely rare (<0.1% allele frequency), correlating with the disease’s low prevalence and absence of a clear founder effect.

Functional studies substantiate a pathogenic role for VIPAS39: zebrafish vipar knockdown recapitulates biliary excretion defects and E-cadherin mis-sorting (PMID:20190753), while yeast two-hybrid and immunoprecipitation assays demonstrate that patient-derived VIPAS39 mutations disrupt endosomal localization and interaction with VPS33B (PMID:23918659). Additionally, Vipas39-deficient mice exhibit abnormal lamellar body biogenesis and impaired skin barrier function, mirroring the ichthyosis in ARC patients (PMID:29409756).

Integration of genetic and experimental data yields strong evidence for the VIPAS39–ARC association. Early genetic testing for VIPAS39 variants in neonates with cholestasis and multisystem involvement can obviate invasive procedures and guide management. Key Take-home: Biallelic VIPAS39 loss-of-function variants cause ARC syndrome, supporting inclusion of VIPAS39 in diagnostic panels.

References

• Orphanet journal of rare diseases • 2024 • VIPAS39 related arthrogryposis-renal dysfunction-cholestasis syndrome-case report and systematic review. PMID:39736737
• Nature genetics • 2010 • Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization. PMID:20190753
• Human molecular genetics • 2013 • Vps33b pathogenic mutations preferentially affect VIPAS39/SPE-39-positive endosomes. PMID:23918659
• Biochimica et biophysica acta. Molecular basis of disease • 2018 • VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function. PMID:29409756

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