Three Austrian patients presented with severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Exome sequencing revealed biallelic mutations in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein which interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen modifying enzyme LH3. Two patients showed the homozygous missense variant p.Gly131Glu, whilst one patient was compound heterozygous for p.Gly131Glu and the splice site mutation c.240-1G>C, previously reported in patients with arthrogryposis renal dysfunction and cholestasis syndrome. The pathogenicity of variant p.Gly131Glu was demonstrated by assessing the interactions of the mutant VPS33B construct and its ability to traffic LH3. Compared with wild-type, p.Gly131Glu mutant VPS33B had reduced coimmunoprecipitation and colocalization with Rab11a and Rab25 and did not rescue LH3 trafficking. Confirming the cell-based experiments, we found deficient LH3-specific collagen lysine modifications in urine and skin fibroblasts of the patients. Additionally, epidermal ultrastructure of the p.Gly131Glu patients mirrored defects in tamoxifen-inducible VPS33B deficient Vps33bfl/fl–ERT2 mice. Both patients and murine models revealed an impaired basement membrane zone and epidermal barrier structure with less prominent hemidesmosomes, a reduced number of anchoring fibrils, insufficiently fixed collagen fibers to the fibrils and aberrant secretion of lamellar bodies. Our results show that p.Gly131Glu mutant VPS33B causes an Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) syndrome.

VPS33B mutations cause ARKID syndrome affecting Rab protein interaction, collagen modification and epidermal structure