Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation (2079del14) in the desmoglein 3 gene.

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J Invest Dermatol 2002 Dec;119(6):1237-43

Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation (2079del14) in the desmoglein 3 gene.

Pemphigus encompasses a group of autoimmune blistering diseases with circulating pathogenic autoantibodies recognizing several proteins, including the desmosomal cadherin, desmoglein 3. Targeted disruption of the Dsg3 gene by homologous recombination (Dsg3tm1stan) in mouse results in fragility of the skin and oral mucous membranes, analogous to the human disease. In addition, the Dsg3tm1stan mice develop phenotypic runting and hair loss, identical to that of the mouse mutant, Dsg3bal-2J. The Dsg3bal-2J mice are homozygous for a 1 bp insertion (2275insT) in the Dsg3 gene resulting in a nonfunctional Dsg3 mRNA. In this study, we characterized an allelic mutation, Dsg3bal-Pas, with clinical features similar to those in Dsg3bal-2J. We have identified a 14 bp deletion in exon 13 of the Dsg3 gene resulting in a frameshift and premature termination codon 7 bp downstream from the site of the deletion and causing a truncation of the desmoglein 3 polypeptide by 199 amino acids, eliminating virtually all of the intracellular domain. We demonstrate that, although a Dsg3 mRNA transcript was detectable in Dsg3bal-Pas skin, the corresponding protein for desmoglein 3 was completely absent in the oral mucosal epithelium of homozygous Dsg3bal-Pas compared with that of +/Dsg3bal-Pas mice. No significant changes in the expression of desmogleins 1 and 2 were detected. To elucidate a potential mechanism causing loss of cell adhesion in the Dsg3bal-Pas mice, we generated a myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein and expressed it in keratinocytes. The myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein was found predominantly in the cytoplasm possibly due to increased proteolytic degradation. Cell surface staining was also detected but was jagged, not linear along the cell-cell border like that observed for the full-length desmoglein 3. The expression of the myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein resulted in a reduction in staining of other desmosomal proteins, including desmoglein 1 and 2, plakophilin 2, and plakoglobin. In addition, the cells expressing myc-tagged truncated Dsg3bal-Pas desmoglein 3 protein underwent dramatic changes in cell morphology and exhibited striking extensive filopodia. Collectively, these data showed that the perturbation of desmoglein 3 found in the Dsg3bal-Pas mice resulted in disadhesion of keratinocytes manifested with blistering phenotype.

J Dermatol 2002 Oct;29(10):661-4

Seventeen cases of alopecia areata: combination of SADBE topical immunotherapy with other therapies.

Topical immunotherapy is effective for severe alopecia areata. However, there are patients with alopecia areata refractory to topical immunotherapy alone. We tried SADBE (squaric acid dibutylester) topical immunotherapy combined with topical dry ice cryotherapy, carpronium chloride (a parasympathetic nerve stimulant) and/or oral cepharanthin (a biscoclaur alkaloid) in alopecia areata refractory to topical SADBE. Seventeen patients with alopecia areata (3 multiple, 3 ophiasis, 5 totalis and 6 universalis) were treated with SADBE in our department in 1999 to 2001. In 3 cases (2 multiple and 1 universalis) out of the 17 cases, cosmetically acceptable regrowth of hair was observed in several months with topical SADBE alone. In the other 14 cases, the SADBE therapy alone for several months (mean: 6.9 months) resulted in no or poor regrowth of hair. However, with subsequent combination therapy of topical SADBE for several months (mean: 7.6 months), satisfactory regrowth of hair was observed in 6 of the 14 cases. Our cases indicate that combination therapy of topical SADBE with other therapies can be a choice for alopecia areata which is refractory to topical SADBE therapy alone.

Br J Dermatol 2002 Apr;146(4):601-8

The hairless gene in androgenetic alopecia: results of a systematic mutation screening and a family-based association approach.

BACKGROUND: Genetic disposition and androgen dependence are important characteristics of the common patterned loss of scalp hair known as androgenetic alopecia (AGA). The genetic factors contributing to AGA are currently unknown. The human hairless gene (HR) has recently been cloned and mutations have been reported in families with autosomal recessive universal congenital alopecia and papular atrichia. The main feature of these disorders is persistent complete absence of hair at or shortly after birth. This suggests that HR is essential and specific for the development of hair. OBJECTIVES: To test the hypothesis that HR may be involved in AGA. METHODS: We systematically screened HR for genetic variability by means of single-strand conformation analysis (SSCA) in 46 unrelated men with AGA. To test for an involvement of HR in the development of AGA, seven common variants were genotyped in 61 families with 93 affected offspring. The results were analysed with the transmission/disequilibrium test (TDT). RESULTS: SSCA showed 15 single nucleotide substitutions: eight missense mutations, four silent mutations and three mutations in exon-flanking intronic sequences. TDT results showed a marginally significant association between AGA and variants 3379-29G/T (P = 0.024) and 2611-68C/T (P = 0.047). These results, however, did not remain significant after applying the conservative Bonferroni correction for multiple testing. CONCLUSIONS: Our results do not provide evidence for a strong involvement of HR in the development of AGA, although a minor role cannot be fully excluded.

Dermatology. 2003;206(3):189-91.

Association between Smoking and Hair Loss: Another Opportunity for Health Education against Smoking?

Besides being the single most preventable cause of significant morbidity and an important cause of death in the general population, tobacco smoking has been associated with adverse effects on the skin. Smoke-induced premature skin ageing has attracted the attention of the medical community, while only recently an observational study has indicated a significant relationship between smoking and baldness. The mechanisms by which smoking causes hair loss are multifactorial and are probably related to effects of cigarette smoke on the microvasculature of the dermal hair papilla, smoke genotoxicants causing damage to DNA of the hair follicle, smoke-induced imbalance in the follicular protease/antiprotease systems controlling tissue remodeling during the hair growth cycle, pro-oxidant effects of smoking leading to the release of pro-inflammatory cytokines resulting in follicular micro-inflammation and fibrosis and finally increased hydroxylation of oestradiol as well as inhibition of the enzyme aromatase creating a relative hypo-oestrogenic state. In view of the psychological impact of androgenetic alopecia on affected men and women, increasing public awareness of the association between smoking and hair loss offers an opportunity for health education against smoking that may be more effective than the link between smoking and facial wrinkles or grey hair, since the latter can be effectively counteracted by current aesthetic dermatologic procedures, while treatment options for androgenetic alopecia are limited.

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