VPS33B – Arthrogryposis, Renal Dysfunction, and Cholestasis 1

Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder caused by biallelic mutations in VPS33B, encoding a Sec1/Munc18 family protein that regulates SNARE-dependent membrane fusion and intracellular trafficking. VPS33B was identified as the causative gene through mapping to 15q26.1 and sequencing in 14 unrelated kindreds, revealing truncating and splicing variants in all affected individuals (PMID:15052268). Affected infants present with congenital joint contractures, renal tubular dysfunction, neonatal cholestasis with low gamma‐glutamyl transpeptidase activity, ichthyosis, platelet defects, severe failure to thrive, and early lethality.

Genetic evidence supports a definitive association. Over 50 unrelated probands across >14 families harbour pathogenic VPS33B variants, including nonsense, frameshift, canonical splice-site, and missense mutations with consistent autosomal recessive inheritance and segregation in consanguineous and multiplex families (PMID:15052268, PMID:31240160). Segregation data include two siblings born to first cousin parents with a novel homozygous missense mutation and prolonged survival, confirming recessive transmission (PMID:31240160).

The variant spectrum is dominated by loss-of-function alleles such as c.84T>A (p.Tyr28Ter), c.319C>T (p.Arg107Ter), c.1509dup (p.Lys504fs), and splice-site mutations (e.g., c.778+2T>G), distributed throughout the transcript with no recurrent founder effect identified. Hypomorphic and missense alleles (e.g., c.1157A>C (p.His386Pro)) have been associated with milder phenotypes and prolonged survival, indicating residual protein function (PMID:31240160).

Functional studies demonstrate that VPS33B deficiency impairs SNARE-mediated vesicle fusion and lamellar granule secretion in epidermal cells, explaining ichthyosis and platelet alpha-granule defects (PMID:18347289). In cell-based assays, certain splice-site and missense variants retain partial interaction with VIPAS39, correlating with attenuated phenotypes (PMID:22753090). Mouse knockouts of hepatic Vps33b recapitulate intrahepatic cholestasis, liver fibrosis, and hepatocellular carcinoma, underscoring a critical role in hepatocyte polarity and bile acid metabolism (PMID:29729199).

No evidence refutes the VPS33B-ARC association or implicates alternative genes in classical ARC syndrome. Discrete alleles in VIPAS39 cause ARC2 but do not overlap with VPS33B-mediated phenotypes.

In summary, convergent genetic and functional evidence conclusively establishes VPS33B as the causative gene for arthrogryposis, renal dysfunction, and cholestasis 1. Comprehensive variant detection of VPS33B is recommended for early diagnosis and genetic counseling. Key Take-home: VPS33B biallelic loss-of-function mutations lead to definitive autosomal recessive ARC syndrome with poor prognosis, though hypomorphic alleles can yield milder disease with prolonged survival.

References

• Nature genetics • 2004 • Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. PMID:15052268
• JIMD reports • 2019 • A novel mutation in VPS33B gene causing a milder ARC syndrome phenotype with prolonged survival. PMID:31240160
• Journal of pediatric gastroenterology and nutrition • 2009 • Clinical characteristics and VPS33B mutations in patients with ARC syndrome. PMID:19274792
• Archives of dermatology • 2008 • Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B. PMID:18347289
• Human mutation • 2012 • Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome. PMID:22753090
• Hepatology (Baltimore, Md.) • 2018 • Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis. PMID:29729199

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