ABSTRACT
The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.
ABSTRACT
Rheumatic heart disease (RHD) is an inflammatory disease that develops following streptococcal infections. IL10 helps to balance immune responses to pathogens. IL10 polymorphisms have been associated with RHD, although results remain inconclusive. Our aim was to investigate the association between IL10 polymorphisms and RHD in Saudi Arabian patients. IL10 promoter polymorphisms (-1082A/G, -829C/T, and -592C/A) were genotyped in 118 RHD patients and 200 matched controls using the TaqMan allelic discrimination assay. There was a significant difference in IL10-1082 genotype frequency between patients and controls (p = 0.01). -1082G allele carriage (GG+GA vs AA) and the (-1082, -819, -592) GCC haplotype carriage were associated with an increased risk of RHD (p = 0.004, OR 2.1, 95% CIs 1.7-3.4 and p = 0.004, OR 2, 95% CIs 1.3-3.4, respectively). The ACC haplotype was associated with a decrease in RHD risk (p = 0.015, OR 0.6, 95% CIs 0.4-0.9). IL10 promoter polymorphisms may play an important role in the development of RHD and provide an opportunity for therapeutic stratification.
