Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification

Robert Gruber,Clare Rogerson,Christian Windpassinger,Blerida Banushi,Anna Straatman-Iwanowska,Joanna Hanley,Federico Forneris,Robert Strohal,Peter Ulz,Debra Crumrine,Gopinathan K Menon,Stefan Blunder,Matthias Schmuth,Thomas Müller,Holly Smith,Kevin Mills,Peter Kroisel,Andreas R Janecke,Paul Gissen

doi:10.1016/j.jid.2016.12.010

Abstract

In this paper, we report three patients with severe palmoplantar keratoderma associated with ichthyosis and sensorineural deafness. Biallelic mutations were found in VPS33B, encoding VPS33B, a Sec1/Munc18 family protein that interacts with Rab11a and Rab25 proteins and is involved in trafficking of the collagen-modifying enzyme LH3. Two patients were homozygous for the missense variant p.Gly131Glu, whereas 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. We demonstrated the pathogenicity of variant p.Gly131Glu by assessing the interactions of the mutant VPS33B construct and its ability to traffic LH3. Compared with wild-type VPS33B, the 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 patients’ urine and skin fibroblasts. Additionally, the 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 epidermal structure, ascribed to aberrant secretion of lamellar bodies, which are essential for epidermal barrier formation. Our results demonstrate that p.Gly131Glu mutant VPS33B causes an autosomal recessive keratoderma-ichthyosis-deafness syndrome.

Highlights

Palmoplantar keratoderma (PPK) denotes hyperkeratosis of palms and soles
The underlying pathology of the skin phenotype in VPS33B deficiency has previously been attributed to defective lamellar body (LB) secretion (Hershkovitz et al, 2008), and Rab11a has recently been shown to be essential for LB biogenesis (Reynier et al, 2016)
We demonstrate here that the p.Gly131Glu variant disrupts the interaction of VPS33B-VIPAR with Rab11a and VPS33B deficiency causes abnormal formation of LB structures in mouse and human epidermis, suggesting that this interaction with Rab11a is important for LB biogenesis

Summary

Introduction

Palmoplantar keratoderma (PPK) denotes hyperkeratosis of palms and soles. The inheritance pattern, phenotype characteristics, and location of the hyperkeratosis as well as the presence of additional extracutaneous features form the basis of classification of different types of PPK (Has and TechnauHafsi, 2016; Lucker et al, 1994; Schiller et al, 2014). Mutations in more than 20 genes have been associated with both isolated and syndromic forms of hereditary PPK. There are two recognized entities of hereditary PPK, which are associated with sensorineural deafness: Vohwinkel syndrome Both are generally inherited in an autosomal dominant manner and caused by mutations in GJB2, encoding a gap junction protein connexin 26. VWS does not include keratitis, and the ichthyosis phenotype

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Conclusion