Low genetic confirmation rate in South Indian subjects with a clinical diagnosis of maturity-onset diabetes of the young (MODY) who underwent targeted next-generation sequencing for 13 genes.

PURPOSE: To screen for maturity-onset diabetes of the young (MODY) variants in subjects with an early age of onset and positive family history of diabetes mellitus. METHODS: 60 subjects with onset of diabetes between 3 and 30 years of age and parental history (onset < 35 years) of diabetes were recruited after excluding autoimmune, pancreatic and syndromic forms of diabetes. Detailed pedigree chart and clinical data were recorded. MODY genetic testing (MODY 1-13) was performed and variant classification was done adhering to the ACMG guidelines. RESULTS: Baseline characteristics of subjects were as follows: mean age of onset of diabetes 19.9 ± 7 years, mean duration of diabetes 6.3 ± 6.8 years, BMI 23.3 ± 3 kg/m2 and C-peptide 1.56 ± 1.06 nmol/l. Four out of sixty (6.6%) were positive for variants classifiable as pathogenic/likely pathogenic: one patient with HNF4Ac.691C > T, (p.Arg231Trp), two with HNF 1A c.746C > A(p.Ser249Ter) and c.1340C > T(p.Pro447Leu), and one with ABCC8 c.4544C > T (p.Thr1515Met). MODY 1 and MODY 3 variants were documented in the paediatric age group (< 18 years). CONCLUSION: A genetic diagnosis of MODY could be confirmed in only 6.6% (4/60) of patients clinically classifiable as MODY. This is less than that reported in clinically diagnosed MODY subjects of European descent. Newly published population data and more stringent criteria for assessment of pathogenicity and younger age of onset of type 2 diabetes in Indians could have contributed to the lower genetic confirmation rate. Apart from variants in the classical genes (HNF1A, HNF4A), a likely pathogenic variant in a non-classical gene (ABCC8) was noted in this study.

Nuclear factor (NF)-κB and its associated pathways are major molecular regulators of blood-induced joint damage in a murine model of hemophilia.

BACKGROUND: The present study was designed to investigate the molecular signaling events from onset of bleeding through the development of arthropathy in a murine model of hemophilia A. METHODS AND RESULTS: A sharp-injury model of hemarthrosis was used. A global gene expression array on joint-specific RNA isolated 3 h post-injury revealed nuclear factor-kappa B (NF-κB) as the major transcription factor triggering inflammation. As a number of genes encoding the cytokines, growth factors and hypoxia regulating factors are known to be activated by NF-κB and many of these are part of the pathogenesis of various joint diseases, we reasoned that NF-κB-associated pathways may play a crucial role in blood-induced joint damage. To further understand its role, we screened NF-κB-associated pathways between 1 h to 90 days after injury. After a single articular bleed, distinct members of the NF-κB family (NF-κB1/NF-κB2/RelA/RelB) and their responsive pro-inflammatory cytokines (IL-1ß/IL-6/IFNγ/TNFα) were significantly up-regulated (> 2 fold, P < 0.05) in injured vs. control joints at the various time-points analyzed (1 h/3 h/7 h/24 h). After multiple bleeds (days 30/60/75/90), there was increased expression of NF-κB-associated factors that contribute to hypoxia (HIF-1α, 3.3-6.5 fold), angiogenesis (VEGF-α, 2.5-4.4 fold) and chondrocyte damage (matrix metalloproteinase-13, 2.8-3.8 fold) in the injured joints. Micro RNAs (miR) that are known to regulate NF-κB activation (miRs-9 and 155), inflammation (miRs-16, 155 and 182) and apoptosis (miRs-19a, 155 and 186) were also differentially expressed (-4 to +13-fold) after joint bleeding, indicating that the small RNAs could modulate the arthropathy phenotype. CONCLUSIONS: These data suggest that NF-κB-associated signaling pathways are involved in the development of hemophilic arthropathy.