VPS33B – Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive multisystem disorder characterized by congenital joint contractures, proximal renal tubular leak, and neonatal cholestasis with low γ-glutamyl transpeptidase activity. Biallelic loss-of-function variants in VPS33B disrupt SNARE-mediated vesicle trafficking in hepatocytes, renal tubular cells, and epidermal keratinocytes, leading to the classic ARC triad and variable skin, neurological, and hematologic manifestations ([PMID:16492441]).

Autosomal recessive inheritance is supported by homozygous or compound heterozygous VPS33B variants identified in over 40 unrelated probands from more than 30 families. Segregation analysis in consanguineous pedigrees, including affected identical twins, confirms co-segregation of VPS33B mutations with disease without reported phenocopies ([PMID:16492441]).

The variant spectrum includes nonsense, frameshift, splice-site, and missense mutations. For example, NM_018668.5(VPS33B):c.971del (p.Lys324ArgfsTer11) has been reported homozygously in a patient with incomplete ARC phenotype ([PMID:16492441]). Multiple recurrent and private alleles underscore allelic heterogeneity.

Functional studies demonstrate that VPS33B deficiency impairs lamellar granule secretion in the epidermis, producing ichthyosis, and disrupts α-SNARE–dependent vesicle fusion in renal and hepatic cells. Ultrastructural analyses reveal entombed lamellar bodies in stratum corneum ([PMID:18347289]), and Vps33b-knockout mice develop ichthyotic skin and cholestasis phenotypes ([PMID:29409756]). Genotype–phenotype correlations, such as partial retention of function in the splice-site variant c.1225+5G>C, predict milder ARC presentations and extended survival ([PMID:22753090]).

No robust conflicting reports dispute VPS33B’s role in ARC; instead, incomplete phenotypes emphasize broad clinical variability. Early molecular diagnosis via targeted or exome sequencing obviates invasive biopsies and enables timely supportive care.

Key Take-home: VPS33B sequencing is essential for diagnosis of ARC syndrome, guiding genetic counseling, prenatal testing, and personalized management of cholestasis, renal dysfunction, and skin disease.

References

• The Journal of Pediatrics • 2006 • VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. PMID:16492441
• Archives of Dermatology • 2008 • Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B. PMID:18347289
• Journal of Pediatric Orthopedics • 2011 • Orthopaedic manifestations of arthrogryposis-renal dysfunction-cholestasis syndrome. PMID:21150740
• Human Mutation • 2012 • Associations among genotype, clinical phenotype, and intracellular localization of trafficking proteins in ARC syndrome. PMID:22753090
• Biochimica et Biophysica Acta • 2018 • VPS33B and VIPAR are essential for epidermal lamellar body biogenesis and function. PMID:29409756

Evidence Based Scoring (AI generated)