Detection of KCNJ11 gene mutations in a family with neonatal diabetes mellitus: implications for therapeutic management of family members with long-standing disease.

BACKGROUND: Activating mutations of potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11), which encodes Kir6.2 (beta-cell adenosine triphosphate-sensitive potassium [K(ATP)] channel subunit), have been associated with neonatal diabetes mellitus (NDM) in different studies. Treatment with oral sulfonylureas in place of exogenous insulin injections results in improved glycemic control in most patients carrying these mutations. Exploration of genetic causes of NDM occurring before the age of 6 months has been proposed as an important issue in identification of monogenic forms of diabetes, which might be critical in their therapeutic management, as a consequence. METHODS: Mutation screening of the KCNJ11 gene was carried out using PCR amplification followed by direct sequencing in three family members: the proband, ND1, diagnosed at 40 days of age (current age 7 years); his sibling, ND2, diagnosed at 2 years of age (current age 14 years); and their father, ND3, diagnosed at 15 years of age (current age 35 years), who had been exclusively treated with insulin. The effect of the E227K mutation was also examined in a homology model of Kir6.2. RESULTS: Our results revealed the presence of the heterozygous missense mutation c. 679 G/A (E227K) in all three patients, who were all able to successfully transfer from insulin injections to an oral sulfonylurea, with improved glycemic control. CONCLUSION: We found that three members of a family with highly variable age of onset of insulin-treated diabetes, diagnosed at 40 days, 2 years, and 15 years of age, all carried the E227K mutation in KCNJ11 and could switch to an oral sulfonylurea. This mutation has been previously reported in patients with permanent and transient NDM, as well as later-onset diabetes; this report adds to the variability in phenotypic presentation and further supports genetic testing in all diabetic members of any family affected by NDM.

Survivin gene polymorphism association with papillary thyroid carcinoma.

Survivin expression is correlated with suppression of apoptosis in human solid tumors. A polymorphism at position -31 (G/C) (rs 9904341) has been associated with cancer risk in several studies. We evaluated the correlation of this polymorphism with the risk of papillary thyroid carcinoma (PTC) in an Irananian population. The cases consisted of patients with PTC (n=123) and normal controls, composed of non-related healthy people (n=131). The frequency of GC or CC genotype in patients with PTC was significantly higher than in the controls [GC+CC vs GG, p=0.02 OR; 1.7, 95%CI (1.05-3.04)]. There was a significant difference between patients with more aggressive clinical manifestations, including lymphatic involvement compared to the controls [GC+CC vs GG, p=0.0006, OR; 3.7, 95%CI (1.6-9.2)]. The presence of C allele was significantly associated with the presence of more profound manifestations, including lymph node involvement, vascular involvement and multifocality.

TGF-ß and IL-23 gene expression in unstimulated PBMCs of patients with diabetes.

The protective effects of TGF-ß have been documented in various autoimmune diseases, mostly in organ-specific autoimmunity including type 1 diabetes mellitus (T1DM). However, TGF-ß also plays a role as a pro-inflammatory mediator by induction of Th17 cytokine production. IL-23 also plays a key role in differentiation of Th17 cells, which are implicated in pathogenesis of autoimmune conditions including T1DM. The aim of this study was to investigate and compare the difference in the level of TGF-ß1 and IL-23 gene expression in unstimulated peripheral blood mononuclear cells (PBMCs) of patients with different forms of diabetes compared with normal healthy controls subjects. Patients with T1DM were grouped as early-onset T1DM (N = 20) with age at diagnosis <18 years and late-onset T1DM (N = 20) with the age at onset >18 years. Patients with T2DM (N = 20) and normal healthy controls (N = 20) were recruited from the same area. TGF-ß1 and IL-23 gene expression in fresh unstimulated PBMCs was determined in each group using quantitative real-time PCR. The results confirmed that a significant difference in TGF-ß1 and IL-23 gene expression was observed in both forms of juvenile-onset T1DM and adult-onset T1DM compared to the controls and T2DM patients. There was no significant difference for TGF-ß gene expression in patients with T2DM and controls. We therefore conclude that our results support the previous data on TGF-ß gene down-regulation in T1DM. Also up-regulation of IL-23 has been observed in T1DM whilst it was down-regulated in T2DM. We also found no significant difference between juvenile-onset and adult-onset T1DM indicating same mechanism might be involved in the pathogenesis of both types. More studies on different cytokines in Th17 pathways are required to further confirm our finding.

Association of survivin gene polymorphism with endometrial cancer.

OBJECTIVE: Survivin is an inhibitor of apoptosis protein, which is up-regulated in endometrial cancer (EC). A promoter region polymorphism (-31G/C) in the survivin gene has been reported as a modulator of gene expression. The aim of this study was to explore the frequency of survivin -31G/C polymorphism in tumor tissues from patients with EC in an Iranian population compared to that of healthy controls. MATERIALS AND METHODS: Paraffin-embedded tissue sections from patients diagnosed with EC (n = 31) and healthy controls (n = 30) were examined. Genotyping for survivin -31G/C polymorphism was performed using polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). RESULTS: The presence of allele C was found to be significantly increased in EC tissues compared to the healthy tissues (GG vs GC + CC, P = 0. 01; OR, 3.6; 95% CI, 1.1-11.9). CONCLUSION: Our data are in keeping with a previous finding regarding the role of survivin gene polymorphism in malignancies. This finding highlights the role of survivin in pathogenesis of various carcinomas, which might have therapeutic implications.

VEGF gene polymorphism association with diabetic foot ulcer.

OBJECTIVE: Functional polymorphisms within vascular endothelial growth factor (VEGF) gene have shown association with various conditions including diabetic neuropathy and retinopathy. In this study we have performed a candidate gene association study in order to examine VEGF gene polymorphism association with diabetic foot ulcer (DFU). METHODS: The study group comprised of type 2 diabetes patients with (N=247) and without (N=241) DFU. Healthy control subjects (N=98) were also recruited from the same area. The ARMS-PCR technique was applied for genotyping of VEGF gene SNPs at positions -7*C/T and -2578*C/A. RESULTS: The frequency of genotype AA was significantly decreased in patients with DFU compared with diabetic subjects without DFU (AA vs CA+CC, p=0.003, OR=0.44, CI=0.24-0.80). Also there was a significant decrease in frequency of A allele in patients with DFU compared to the controls (p=0.02, OR=0.68, CI=0.48-0.96). CONCLUSION: It seems that lower frequency of A allele in patients with DFU is conferring a protective effect which might be as a result of increased angiogenesis in patients carrying this allele.