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N. KÜHN-VELTEN, W. STAIB, B.-E. BRAUN and M. KRIEG

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E Potter, S Braun, U Lehmann and G Brabant

OBJECTIVE: Plakoglobin (Pg) is the only cytoplasmic protein component common to both junctional complexes mediating cell-cell adhesion, adherens junctions and desmosomes. In these complexes Pg appears to act as a linker protein anchoring transmembrane proteins of the cadherin superfamily to the actin cytoskeleton and intermediate filament system respectively. Intercellular adhesion is frequently disturbed in skin diseases and in carcinomas, enabling tumour progression and metastasis. Whereas Pg expression is lost in some thyroid tumours and carcinoma cell lines, little information on Pg gene regulation is currently available owing to a lack of promoter studies. DESIGN AND METHODS: We have cloned and sequenced genomic DNA from a human library that resulted in 979 bp upstream of the published Pg cDNA. The transcriptional start was mapped by rapid amplification of cDNA ends. Methylation-specific PCR of bisulfite-modified cell line DNA was applied to probe the methylation status of a promoter-associated CpG island. Reporter-gene constructs of various promoter fragments were transiently transfected in thyroid carcinoma cell lines and their activities were determined by luciferase measurements. RESULTS AND CONCLUSIONS: A 1 kb DNA fragment harbouring a functional promoter of the human Pg gene was cloned and characterized. The sequence lacks a canonical TATA box, but contains putative CCAAT boxes as well as various putative binding sites for transcription factors, among them SP1 and AP2, proximal to the transcriptional start. Considerable promoter activity was found in thyroid cell lines and deletion analysis indicated that a 300 bp region proximal to the 5'-untranslated region of the mRNA represents the minimal promoter of the human Pg gene. As cells lacking endogenous Pg expression were found to contain methylated CpG dinucleotides in a CpG island located around the transcriptional start site, it is suggested that epigenetic mechanisms such as DNA methylation contribute to dysregulated Pg expression.

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G Speer, K Cseh, G Winkler, P Vargha, E Braun, I Takacs and P Lakatos

OBJECTIVE: We studied the significance of BsmI restriction enzyme polymorphism of the vitamin D receptor (VDR) gene and the XbaI and PvuII polymorphisms of the estrogen receptor (ER) gene in patients with type 2 diabetes (n=49), android type obesity with normal carbohydrate metabolism (n=29) and healthy controls (n=138). METHODS: The distribution of genotypes in the study groups, as well as their relationship to fasting and 1 h postprandial serum C-peptide levels were analyzed. RESULTS: Postprandial serum C-peptide levels of BB genotypes were significantly higher in the diabetes and obese groups (6.18+/-5.09 ng/ml) compared with other genotypes (2.71+/-2.45 vs. 1.72+/-1.97 ng/ml, respectively, P=0.05). Among patients with type 2 diabetes and obese subjects, the XX allelic variant of the ER gene was more frequent (P=0.00015). Postprandial C-peptide levels of subjects exhibiting XX genotype were significantly lower compared with those with Xx genotype (1.67+/-2.16 vs. 3.8+/-3.72 ng/ml, P=0.021). The BBXx allelic combination of the VDR/ER receptor genes was less frequent in diabetic patients than in healthy subjects or in obese patients. The BBXx genotype was associated with significantly elevated postprandial C-peptide levels in all subjects compared with other combinations (9.65+/-3.14 vs. 1.35+/-2.82 ng/ml, P=0.003). No difference was found in the distribution of the PvuII polymorphism of the ER gene or in the association with the C-peptide levels among study groups. CONCLUSION: Polymorphisms of the VDR/ER receptor genes might play a role in the pathogenesis of type 2 diabetes by influencing the secretory capacity of beta-cells.

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Elodie Fiot, Delphine Zénaty, Priscilla Boizeau, Jérémie Haignere, Sophie Dos Santos, Juliane Léger and the French Turner Syndrome Study Group

Objective

Turner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.

Design and methods

This national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).

Results

Median age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders.

Conclusion

These data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.