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Defective Lamellar Granule Secretion in Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome Caused by a Mutation in VPS33B
Dov Hershkovitz, MD;
Hannah Mandel, MD;
Akemi Ishida-Yamamoto, MD;
Ilana Chefetz, MSc;
Bayan Hino, MD;
Anthony Luder, MD;
Margarita Indelman, MSc;
Reuven Bergman, MD;
Eli Sprecher, MD, PhD
Arch Dermatol. 2008;144(3):334-340.
Background Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare and usually fatal metabolic autosomal recessive disorder, which has recently been shown to result from mutations in VPS33B located on chromosome 15q26.1. Neurological signs and ichthyosis almost invariably accompany the disease.
Observations We assessed a consanguineous family with 2 identical twins affected with ARC syndrome. Complete sequencing of the VPS33B gene revealed a homozygous missense mutation (D234H), which segregated with the disease in the affected family. The mutation causes aberrant splicing, resulting in the skipping of exon 9 or exons 9 and 10. VPS33B encodes a homologue of the class C yeast vacuolar protein-sorting molecule, Vps33, which regulates soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein–mediated vesicle-to-target fusion, necessary for secretion to occur. Lamellar granules, forming a specialized vesicular system in the epidermal upper layers, are usually secreted at the boundary between granular and lower cornified cell layers. However, ultrastructural examination of the skin in ARC syndrome revealed many entombed lamellar granules in the cornified cells.
Conclusions The present observations indicate that VPS33B deficiency results in abnormal secretion of lamellar granules, which underlies ichthyosis in ARC syndrome. These data underscore the importance of SNARE-mediated vesicle fusion during normal epidermal differentiation.
Author Affiliations: Department of Dermatology and Laboratory of Molecular Dermatology (Drs Hershkovitz, Bergman, and Sprecher and Ms Indelman) and Department of Pediatrics B and Metabolic Unit (Dr Mandel), Meyer Children's Hospital, Rambam Health Care Campus, Haifa, Israel; Faculty of Medicine (Drs Mandel, Chefetz, Hino, Luder, Bergman, and Sprecher) and Rappaport Institute for Research in the Medical Sciences (Dr Sprecher), Technion–Israel Institute of Technology, Haifa; Department of Dermatology, Asahikawa Medical College, Asahikawa, Japan (Drs Ishida-Yamamoto and Hino); and Pediatric Department, Ziv Medical Center, Safed, Israel (Dr Lunder).
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