title: Autosomal Recessive Keratoderma-Ichthyosis-Deafness (ARKID) Syndrome Is Caused by VPS33B Mutations Affecting Rab Protein Interaction and Collagen Modification.
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-ERT2mice. 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.
authors.affiliation: Department of Dermatology, Medical University of Innsbruck, Innsbruck, Austria; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; Institute of Child Health, University College London, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Rogerson
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; Institute of Child Health, University College London, London, UK.
authors.forename: Blerida
authors.initials: B
authors.lastname: Banushi
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; Institute of Child Health, University College London, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Straatman-Iwanowska
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; Institute of Child Health, University College London, London, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Hanley
authors.affiliation: The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Forneris
authors.affiliation: Department of Dermatology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Strohal
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ulz
authors.affiliation: Department of Dermatology, Veterans Affairs Medical Center, University of California, San Francisco, California, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.affiliation: California Academy of Sciences, San Francisco, California, USA.
authors.forename: Gopinathan K
authors.initials: GK
authors.lastname: Menon
authors.affiliation: Department of Dermatology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Blunder
authors.affiliation: Department of Dermatology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK.
authors.forename: Holly
authors.initials: H
authors.lastname: Smith
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Mills
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Kroisel
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria; Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: andreas.janecke@i-med.ac.at.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, London, UK; Institute of Child Health, University College London, London, UK; Inherited Metabolic Diseases Unit, Great Ormond Street Hospital, London, UK. Electronic address: p.gissen@ucl.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D003094:Collagen / Q000378:metabolism; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000175:diagnosis / Q000235:genetics*; D007645:Keratoderma, Palmoplantar / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D011379:Prognosis; D035583:Rare Diseases; D012494:Sampling Studies; D013577:Syndrome; D033921:Vesicular Transport Proteins / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000099193:rab11 GTP-Binding Proteins
chemical_list: D003094:Collagen; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C411584:VPS33B protein, human