Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

: The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

DIABETIC COMPLICATIONS AND RISK FACTORS IN RECENTLY DIAGNOSED TYPE II DIABETES: A CASE-CONTROL STUDY

&nbsp; Abstract INTRODUCTION: Due to a worldwide increase in the incidence of type II diabetes, it will likely continue to be a major cause of morbidity and mortality in the future. Given that usually a mean of 4-7 years has passed from the initial onset of type II diabetes until the time of diagnosis, a great number of patients have already been affected by one or more diabetic complications by the time of diagnosis. Our objective was to evaluate the prevalence of diabetic complications and risk factors in recently diagnosed type II diabetic patients in the city of Mashhad, Northeast Iran. methods: This cross-sectional prevalence study was performed between March, 2002 and September, 2002. The study group included 200 type II diabetics whose disease had been diagnosed within one year prior to the start of our study. The collected data included medical history, physical examination and clinical tests, including urinalysis (for evaluation of macroproteinuria), blood sampling (for evaluation of serum glucose and lipid levels), and electrocardiography (EKG). Several common indicators of diabetic complications were analyzed. results: Of the 200 patients studied, 66 were male and 134 were female. The mean age of the patients was 52.2 years for men and 46.8 for women at the time of diagnosis. Overall, 74.2% of the patients were shown to have been affected by one or more diabetic complications prior to diagnosis with type II diabetes. CONCLUSIONS: Formulating a new screening program may help us diagnose type II diabetes earlier and control it more effectively. This may lead to a reduction in morbidity and mortality in type II diabetes patients. &nbsp; &nbsp; Keywords: Type II diabetes mellitus, retinopathy, neuropathy, nephropathy, macrovascular complications, body mass index.</div