No abstract

Spinocerebellar ataxia type-12 (SCA-12) is a neurodegenerative disease that exhibits a unique progressive tremor/ataxia syndrome caused by a triplet (CAG) repeat expansion in the 5' UTR region of PPP2R2B. So far, no study has been done to investigate the pathological hallmarks using the appropriate disease model. Therefore, we aimed to establish human iPSC-derived SCA12 neuronal cell lines to study the cellular pathological mechanisms induced by CAG expansion. We found that expanded CAG in PPP2R2B transcript causes the formation of RNA foci inside the nucleus of the patient-derived neural stem cells, which in turn may sequester many nuclear proteins, and inhibit their necessary functions. The ectopic expression of this expanded CAG transcript from PPP2R2B accelerates non-canonical Repeat Associated Non-AUG (RAN) translation in multiple frames in HEK293T cells, which was further validated in patient-derived neural stem cells using novel antibodies. Next, an RNA-pull down assay followed by mass-spectrometric-based protein detection analysis of patient and control-derived neural stem cells identified crucial proteins involved in protein homeostasis, vesicular trafficking, ion channels signaling, etc. shedding light on the mechanistic relationship between RAN translation and RNA foci, and their relative contributions to cellular dysfunction. We also performed the transcriptome sequencing of the diseased and control neurons which identified a network of crucial transcription factors affecting neural fate, in addition to alteration of various signaling pathways affecting neuronal and nervous system development and function. Altogether, this study identifies the molecular signatures of spinocerebellar ataxia type-12 disorder using patient-derived neuronal cell lines, wherein RNA foci and RAN protein accumulation impact the functioning of crucial intracellular pathways. Furthermore, overlapping of these pathways in the same cell lines demonstrates the critical partaking of two modifiers in disease progression emphasizing the new therapeutic strategies that target both processes in repeat expansion disorders.

Purpose:There have been concerted efforts towards cataloging rare and deleterious variants in different world population using high throughput genotyping and sequencing based methods. The Indian populations are underrepresented or its information w.r.t. clinically relevant variants are sparse in public datasets. The aim of this study was to estimate the burden of monogenic disease causing variants in Indian populations. Towards this, we have assessed the frequency profile of monogenic phenotype associated ClinVar variants. Methods: The study utilized genotype dataset (global-screening-array, Illumina) from 2795 individuals (multiple in-house genomics cohorts) representing diverse ethnic and geographically distinct Indian populations. Results: Of the analyzed variants from GSA,˜12% were found to be informative and were either not known earlier or underrepresented in public databases in terms of their frequencies. These variants were linked to disorders, viz. Inborn-errors of Metabolism, Monogenic-diabetes, hereditary cancers and various other hereditary conditions. We have also shown that our study cohort is genetically better representatives of Indian populations than its representation in1000 genome project (South-Asians). Conclusion: We have created a database, ClinIndb [(http://clinindb.igib.res.in) and (https://databases.lovd.nl/shared/variants?searchowned by =%3D%22Mohamed%20Faruq%22)], to help clinicians and researchers in diagnosis, counseling and development of appropriate genetic screening tools relevant to the Indian populations and Indians living abroad.

NATURE October 8, 1955 VOL 176 curves relating to two glasses, one meltfld from commercial TeO, and the other melted from purified TeO 2 , are shown in Fig. 1. Chemical analysis of these glasses showed that they contained respectively -0•004 per cent and -0•001 per cent iron, expressed as Fe 2 O 3 • Examination of the curves shows that with increasing purity of the glass, the ultraviolet absorption edge shifts towards shorter wavelengths. This is consistent with a decrease in proportion of ferric iron in the glass. Thus, it is concluded that the yellow-green colour of tellurite glasses melted from commercial materials is due to traces of iron impurities, and that the coloration may be greatly diminished by using a purer form of TeO 2 •It should be pointed out that the refractive index of the glass of composition BeO.8TeO 2 is approximately 2 • I. Thus, there occurs during the transmission measurements a loss by reflexion at both surfaces amounting to about 24 per cent. This explains, in part, why the overall transmission of the glasses is low.