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PURPOSE: Multiple Endocrine Neoplasia (MEN) is a group of familial cancer syndromes that encompasses several types of endocrine tumors differentiated by genetic mutations in RET, MEN1 and CDKN1B genes. Accurate diagnosis of MEN subtypes can thus be performed through genetic testing. However, MEN variants remain largely understudied in Indian populations. Additionally, few dedicated resources to understand these disorders currently exist. METHODS: Using the gold-standard ACMG/AMP guidelines, we systematically classified variants reported across the three genes in the IndiGen dataset, and established the genetic epidemiology of MEN in the Indian population. We further classified ClinVar and Mastermind variants and compiled all into a database. Finally, we designed a multiplex primer panel for rapid variant identification. RESULTS: We have established the genetic prevalence of MEN as the following: 1 in 1026 individuals is likely to be afflicted with MEN linked with pathogenic RET mutations. We have further created the MAPVar database containing 3280 ACMG-classified variants freely accessible at: https://clingen.igib.res.in/MAPVar/ . Finally, our NGS primer panel covers 33 exonic regions across two pools through 38 amplicons with a total amplified region of 65 kb. CONCLUSION: Our work establishes that MEN is a prevalent disorder in India. The rare nature of Indian variants underscores the need of genomic and functional studies to establish a more comprehensive variant landscape. Additionally, our panel offers a means of cost-effective genetic testing, and the MAPVar database a ready reference to aid in a better understanding of variant pathogenicity in clinical as well as research settings.
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Oligodendrocytes, crucial myelinating glia in the central nervous system, play a vital role in maintaining axonal integrity and facilitating efficient nerve impulse conduction. The degradation of myelin in oligodendrocytes has been implicated in Alzheimer's disease (AD) and cognitive dysfunction. Interestingly, individuals with Type 2 Diabetes (T2D) have a significantly higher likelihood of developing cognitive impairment, possibly due to insulin resistance and glucose toxicity within the central nervous system (CNS). However, the precise relationship between these two disorders remains elusive. Our study proposes a potential link between T2D and AD, involving Cdk5-mediated breakdown of oligodendrocyte myelin and neuroinflammation. In the context of T2D, glucose toxicity in oligodendrocytes leads to heightened Cdk5 kinase activity and cPLA2 hyperactivation, resulting in chronic inflammation and myelin deterioration. This myelin breakdown in oligodendrocytes is thought to contribute to the development of AD and cognitive dysfunction. Notably, the administration of a Cdk5 inhibitor (TFP5) effectively alleviates neuroinflammation and myelin degradation. Moreover, our findings demonstrate heightened activity of Cdk5, cPLA2, and phospho-cPLA2 levels in the brain of a mouse model with Type 2 Diabetes (T2D). Hence, our findings suggest that targeting Cdk5 could be a promising therapeutic strategy to counteract AD pathogenesis in T2D-related conditions.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Vaina de Mielina/metabolismo , Enfermedades Neuroinflamatorias , Oligodendroglía/metabolismo , Fosfolipasas A2 Citosólicas/metabolismoRESUMEN
The present investigation was conducted to assess the nutritional diverseness and identify novel genetic resources to be utilized in chickpea breeding for macro and micro nutrients. The plants were grown in randomized block design. Nutritional and phytochemical properties of nine chickpea genotypes were estimated. The EST sequences from NCBI database were downloaded in FASTA format, clustered into contigs using CAP3, mined for novel SSRs using TROLL analysis and primer pairs were designed using Primer 3 software. Jaccard's similarity coefficients were used to compare the nutritional and molecular indexes followed by dendrograms construction employing UPGMA approach. The genotypes PUSA-1103, K-850, PUSA-1108, PUSA-1053 and the EST-SSR markers including the 5 newly designed namely ICCeM0012, ICCeM0049, ICCeM0067, ICCeM0070, ICCeM0078, SVP55, SVP95, SVP96, SVP146, and SVP217 were found as potential donor/marker resources for the macro-micro nutrients. The genotypes differed (p < 0.05) for nutritional properties. Amongst newly designed primers, 6 were found polymorphic with median PIC (0.46). The alleles per primer ranged 1 to 8. Cluster analysis based on nutritional and molecular diversities partially matched to each other in principle. The identified novel genetic resources may be used to widen the germplasm base, prepare maintainable catalogue and identify systematic blueprints for future chickpea breeding strategies targeting macro-micro nutrients.
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Cicer , Cicer/genética , Marcadores Genéticos , Fitomejoramiento , Genotipo , Repeticiones de Microsatélite/genética , Etiquetas de Secuencia ExpresadaRESUMEN
MicroRNAs (miRNA) are a class of small non-coding RNA, roughly 21-22 nucleotides in length, which are master gene regulators. These miRNAs bind to the mRNA's 3' - untranslated region and regulate post-transcriptional gene regulation, thereby influencing various physiological and cellular processes. Another class of miRNAs known as mitochondrial miRNA (MitomiRs) has been found to either originate from the mitochondrial genome or be translocated directly into the mitochondria. Although the role of nuclear DNA encoded miRNA in the progression of various neurological diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. is well known, accumulating evidence suggests the possible role of deregulated mitomiRs in the progression of various neurodegenerative diseases with unknown mechanism. We have attempted to outline the current state of mitomiRs role in controlling mitochondrial gene expression and function through this review, paying particular attention to their contribution to neurological processes, their etiology, and their potential therapeutic use.