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

Abstract

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.

• Authors: Dov Hershkovitz, Hannah Mandel, Akemi Ishida-Yamamoto, Ilana Chefetz, Bayan Hino, Anthony Luder, Margarita Indelman, Reuven Bergman, Eli Sprecher
• Journal: Archives of dermatology (Arch Dermatol) Vol. 144 Issue 3 Pg. 334-40 (Mar 2008) ISSN: 1538-3652 [Electronic] United States
• PMID: 18347289 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• VPS33B protein, human
• Vesicular Transport Proteins
• RNA
• DNA

Topics

• Arthrogryposis (diagnosis, genetics)
• Cholestasis (genetics)
• Consanguinity
• DNA (analysis)
• DNA Primers
• Diagnosis, Differential
• Diseases in Twins (genetics)
• Female
• Humans
• Ichthyosis (genetics)
• Infant
• Israel
• Kidney Diseases (genetics)
• Mutation
• Pedigree
• Polymerase Chain Reaction
• RNA (analysis)
• Reverse Transcriptase Polymerase Chain Reaction
• Syndrome
• Twins
• Vesicular Transport Proteins (genetics)
• White People (genetics)