Publications

Mutations in the myofibrillogenesis regulator gene (MR-1) causes paroxysmal non -kinesigenic dyskinesia (PNKD) characterized by episodic (paroxysmal) attacks of any combination of chorea, dystonia and athetosis ( MR-1/PNKD) [ 1 ]. This gene is transcribed into three alternatively spliced isoforms: long (MR-1L), medium (MR-1M) and small (MR-1S) [ 2 , 3 ]. Three mutations namely, A7V, A9V and A33P have been described in the N-terminal region common to MR-1L and MR-1S, but not MR-1M and are reported to segregate with the disease in unrelated PNKD families [ 3 , 4 ]. PNKD mutations may also be a cause for familial Tourette syndrome

Snigdha Majumder, Rakshit Shah, Jisha Elias, Malini Manoharan, Priyanka Shah, Anjali Kumari, Papia Chakraborty, Vasumathi Kode, Yogesh Mistry, Karunakaran Coral, Bharti Mittal, Sakthivel Murugan SM, Lakshmi Mahadevan, Ravi Gupta, Amitabha Chaudhuri & Arati Khanna-Gupta. Lynch Syndrome (LS) is an inherited heterozygous autosomal dominant disorder which predisposes affected individuals to the risk of developing colorectal cancer (CRC) as well as to endometrial carcinomas, tumours of the stomach, small intestines, ureter, brain, pelvis and prostate among others1. It is the most common hereditary CRC syndrome accounting for 2–5% of all CRCs. In the developed world, the estimated disease frequency ranges from 1:370 to 1:20002 but no prevalence details have been officially reported from developing nations to date. In India, while the overall incidence of CRC is comparatively lower than in the west, a large percentage of patients develop CRC before the age of 45 with a higher proportion (10–15%) of LS-CRC cases3.

“Background Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion. Methods Multiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene. Results The study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527-2A > T as a second allele. Conclusion This is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene.”””

Indigenous cattle of India belong to the species, Bos indicus and they possess various adaptability and production traits. However, little is known about the genetic diversity and origin of these breeds. To investigate the status, we sequenced and analyzed the whole mitochondrial DNA (mtDNA) of seven Indian cattle breeds. In total, 49 single-nucleotide variants (SNVs) were identified among the seven breeds analyzed. We observed a common synonymous SNV in the COII gene (m.7583G > A) of all the breeds studied. The phylogenetic analysis and genetic distance estimation showed the close genetic relationship among the Indian cattle breeds, whereas distinct genetic differences were observed between Bos indicus and Bos taurus cattle. Our results indicate a common ancestor for European Zwergzebu breed and South Indian cattle. The estimated divergence time demonstrated that the Bos indicus and Bos taurus cattle lineages diverged 0.92 million years ago. Our study also demonstrates that ancestors of present zebu breeds originated in South and North India separately ∼30,000 to 20,000 years ago. In conclusion, the identified genetic variants and results of the phylogenetic analysis may provide baseline information to develop appropriate strategies for management and conservation of Indian cattle breeds.

“””Introduction: Noninvasive prenatal testing (NIPT) is a reliable screening method for fetal aneuploidy detection of trisomy 18, 13, 21 along with few sex chromosome abnormalities monosomy X, XXX, XXY (Klinefelter), XYY (Jacob) syndromes and certain microdeletions which include cri-du-chat, DiGeorge, 1p36, Angelman, and Prader-Willi syndromes in comparison to the available screening methods. Prenatal screening of Turners syndrome is possible by ultrasound in certain conditions only. Recently benefits of early detection and treatment of Turners syndrome has been emphasized, enforcing on accurate and early screening prenatally. Case details: The current case emphasizes on the reliability of NIPT testing which comes with an advantage of early screening. A 24-year-old primi gravida was referred for NIPT as she tested for high risk on biochemical screening. The Panorama™ NIPT results showed low risk for trisomies, 21, 18, and 13 but high risk of monosomy X and was advised confirmatory amniocentesis. The fluorescence in situ hybridization (FISH) report revealed no numerical abnormality detected for any of the five chromosomes tested. On receiving this discordant report, the sample was rerun for NIPT, to rule out any laboratory-related issues. The result obtained on a rerun was consistent with the first report and showed monosomy X again. The karyotype report was available three weeks later and a rare variant of Turners syndrome was identified. Discussion: Panorama™ NIPT considers single nucleotide polymorphisms spread across the chromosomes for analysis, different variants of aneuploidy can be picked up in comparison to FISH, similar to the current case wherein it could not as it was a centromeric probe. Reported first case of X chromosome variant detected by NIPT confirmed by karyotyping, missed by FISH.”””

Tobacco usage is a known risk factor associated with development of oral cancer. It is mainly consumed in two different forms (smoking and chewing) that vary in their composition and methods of intake. Despite being the leading cause of oral cancer, molecular alterations induced by tobacco are poorly understood. We therefore sought to investigate the adverse effects of cigarette smoke/chewing tobacco exposure in oral keratinocytes (OKF6/TERT1). OKF6/TERT1 cells acquired oncogenic phenotype after treating with cigarette smoke/chewing tobacco for a period of 8 months. We employed whole exome sequencing (WES) and quantitative proteomics to investigate the molecular alterations in oral keratinocytes chronically exposed to smoke/ chewing tobacco. Exome sequencing revealed distinct mutational spectrum and copy number alterations in smoke/ chewing tobacco treated cells. We also observed differences in proteomic alterations. Proteins downstream of MAPK1 and EGFR were dysregulated in smoke and chewing tobacco exposed cells, respectively. This study can serve as a reference for fundamental damages on oral cells as a consequence of exposure to different forms of tobacco.

Methylglyoxal (MG) is a predominant precursor for advanced glycation end products (AGEs) due to its protein glycation reactions, which are the major causes of diabetic complications. MG is explored as a significant biomarker towards the prediction of diabetic complications. With this background, a non-enzymatic electrochemical biosensor has been developed to detect MG in human blood plasma samples. Microwave synthesized V2O5 nanoplates were used as interface material in the fabrication of modified gold (Au) working electrode for electrochemical MG biosensor. Orthorhombic crystal structured V2O5 with an oxidation state of +5 exhibited specific MG sensing performance. Cyclic voltammetry and amperometry studies confirmed the electrocatalytic nature of V2O5 nanoplates modified Au electrode in the detection of MG. Non-enzymatic V2O5 modified Au electrode showed a sensitivity of 4.519µAµM-1 with a linear range of 3-30µM, limit of detection (LOD) of 0.24µM, limit of quantification (LOQ) of 0.80µM and a response time less than 8s towards MG. The lifetime and percentage recovery of the sensor was found to be 25 days (90%) and 102.5-108.7% respectively.

Currently approved checkpoint inhibitors are antibodies that block the function of three key proteins expressed on the surface of T cells: CTLA-4, PD-1 and PD-L1. Under normal conditions, these proteins function as brakes to prevent immune-related toxicity from arising because of persistent T cell activity. Cancer hijacks this essential function of immune homeostasis to protect itself from immune-mediated elimination [1, 2]. By expressing high levels of PD-L1, tumor cells engage PD-1 receptors on T cells, suppressing their anti-tumor activity and escaping T cell-mediated killing. By blocking PD-1 and PD-L1 signaling, the checkpoint inhibitors remove the brakes on T cells imposed by the tumor and enhance their anti-tumor activity [3].

Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive form of primary immunodeficiency disorder (PID) characterized by the deficiency of MHC class II molecules. This deficiency affects the cellular and humoral immune response by impairing the development of CD4+ T helper (Th) cells and Th cell-dependent antibody production by B cells. Affected children typically present with severe respiratory and gastrointestinal tract infections. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy available for treating these patients. This is the first report from India wherein we describe the clinical, immunological, and molecular findings in five patients with MHC class II deficiency. Our patients presented with recurrent lower respiratory tract infection as the most common clinical presentation within their first year of life and had a complete absence of human leukocyte antigen-antigen D-related (HLA-DR) expression on B cells and monocytes. Molecular characterization revealed novel mutations in RFAXP, RFX5, and CIITA genes. Despite genetic heterogeneity, these patients were clinically indistinguishable. Two patients underwent HSCT but had a poor survival outcome. Detectable level of T cell receptor excision circles (TRECs) were measured in our patients, highlighting that this form of PID may be missed by TREC-based newborn screening program for severe combined immunodeficiency.

“””Background Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. Methods In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed. Results We found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6–1 that may contribute to development of MODY. Functional assessment of the NKX6–1 variants showed that they are functionally impaired. Conclusions Our findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6–1, and these require further validation.”””