Defective lamellar granule secretion in arthrogryposis, renal dysfunction, and cholestasis syndrome caused by a mutation in VPS33B.
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.


METHODS
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.
Hershkovitz
Dov
D
Laboratory of Molecular Dermatology, Department of Dermatology, Rambam Medical Center, PO Box 9602, Haifa 31096, Israel.
Mandel
Hannah
H
Ishida-Yamamoto
Akemi
A
Chefetz
Ilana
I
Hino
Bayan
B
Luder
Anthony
A
Indelman
Margarita
M
Bergman
Reuven
R
Sprecher
Eli
E
D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D002779:Cholestasis / Q000235:genetics*; D003241:Consanguinity; D004247:DNA / Q000032:analysis; D017931:DNA Primers; D003937:Diagnosis, Differential; D004200:Diseases in Twins / Q000235:genetics*; D005260:Female; D006801:Humans; D007057:Ichthyosis / Q000235:genetics*; D007223:Infant; D007557:Israel; D007674:Kidney Diseases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D014427:Twins; D033921:Vesicular Transport Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics
D017931:DNA Primers; C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins; D012313:RNA; D004247:DNA