Human Molecular Genetics, 2002, Vol. 11, No. 17 2005-2014
© 2002 Oxford University Press
Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations
1Centre for Cutaneous Research, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, Whitechapel, London E1 2AT, UK, 2Light Microscopy, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, UK and 3Bristol Dermatology Centre, Bristol Royal Infirmary, Bristol BS2 8HW, UK
Received April 16, 2002; Revised June 20, 2002; Accepted June 22, 2002
Distinct germline mutations in the gene (GJB3) encoding connexin 31 (Cx31) underlie the skin disease erythrokeratoderma variabilis (EKV) or sensorineural hearing loss with/without peripheral neuropathy. Here we describe a number of functional analyses to investigate the effect of these different disease-associated Cx31 mutants on connexon trafficking and intercellular communication. Immunostaining of a biopsy taken from an EKV patient harbouring the R42P mutation revealed sparse epidermal staining of Cx31, and, when present, it had a perinuclear localization. Transfection and microinjection studies in both keratinocytes and fibroblast cell lines also demonstrated that R42P and four other EKV-associated mutant Cx31 proteins displayed defective trafficking to the plasma membrane. The deafness/neuropathy only mutant 66delD had primarily a cytoplasmic localization, but some protein was visualized at the plasma membrane in a few transfected cells. Both 66delD- and R32W-Cx31/EGFP proteins had significantly impaired dye transfer rates compared to wild-type Cx31/EGFP protein. A striking characteristic feature observed with the dominant skin disease Cx31 mutations was a high incidence of cell death. This was not observed with wild-type, R32W 66delD Cx31 proteins. In conclusion, we have identified some key cellular phenotypic differences with respect to disease-associated Cx31 mutations.
* To whom correspondence should be addressed. Tel: +44 2078827167; Fax: +44 2078827171; Email: kelsell{at}cancer.org.uk
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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