Genetic heterogeneity of mitochondrial genome in thiamine deficient Leigh syndrome patients.

In our previously published study, we cared for 165 thiamine deficient Leigh syndrome (LS) patients who presented in acute life threatening conditions with severe neurological abnormalities. However the molecular basis for this atypical phenotype was not explored. This study is an effort to undermine the possible molecular defects in mitochondria of those patients and put-forth an explanation towards this clinical presentation. Protein coding genes of mitochondrial (mt) DNA were sequenced in total 165 LS patients and 94 age matched controls. To understand their pathogenic significance, nucleotide variations were also studied using various in-silico tools. Histochemical and electron microscopic analysis was also done in tissue samples obtained from 23 patients. We observed a very high level of genetic heterogeneity across the mt DNA of all these patients. In the concordance of published literature we also observed a large number of variations in ND5 gene (hot spot for LS). We also observed a total 13 nucleotide variations across COX genes, which is otherwise not common in LS. As per in-silico analysis, many of these variations were suggested to be pathogenic. Histochemical and electron microscopic studies also suggested the defects in the mitochondria of these patients. As these patients were thiamine deficient, hence we propose that genetic defects and thiamine deficiency may together severely affect the ATP levelof these patients, leading to acute and life threatening clinical presentation. Present study has opened up many avenues for further research towards understanding the genetic basis and possible role of thiamine deficiency in LS patients.

Associations of FTO and MC4R Variants with Obesity Traits in Indians and the Role of Rural/Urban Environment as a Possible Effect Modifier.

Few studies have investigated the association between genetic variation and obesity traits in Indian populations or the role of environmental factors as modifiers of these relationships. In the context of rapid urbanisation, resulting in significant lifestyle changes, understanding the aetiology of obesity is important. We investigated associations of FTO and MC4R variants with obesity traits in 3390 sibling pairs from four Indian cities, most of whom were discordant for current dwelling (rural or urban). The FTO variant rs9939609 predicted increased weight (0.09 Z-scores, 95% CI: 0.03, 0.15) and BMI (0.08 Z-scores, 95% CI: 0.02, 0.14). The MC4R variant rs17782313 was weakly associated with weight and hip circumference (P < .05). There was some indication that the association between FTO and weight was stronger in urban than that in rural dwellers (P for interaction = .03), but no evidence for effect modification by diet or physical activity. Further studies are needed to investigate ways in which urban environment may modify genetic risk of obesity.