Browsing by Author "Souradip Chatterjee"

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Identification and molecular characterization of two recurrent missense mutations in the RS1 gene in two families with X-linked retinoschisis from North India
(John Wiley and Sons Inc, 2023) Souradip Chatterjee; Shashank Gupta; Laxmi Kirola; Abhishek Chandra; Ashim Mukherjee; Mousumi Mutsuddi
X-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein-coding region of RS1 was screened by PCR-Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina. © 2023 Wiley Periodicals LLC.
Identification of a compound heterozygous mutation in GDAP1 gene in a consanguineous South Indian family with Charcot–Marie–Tooth (CMT) Disease
(Springer Nature, 2025) Laxmi Kirola; Deepika Srivastava Joshi; Souradip Chatterjee; Madhusudan Tapadia; Ashim Mukherjee; M. Mutsuddi
Background: Charcot–Marie–Tooth (CMT) is a clinically, electro-physiologically, and genetically heterogenous group of muscle disease which is also known as hereditary motor and sensory neuropathy. Autosomal recessive forms of CMT type 4A have been reported with either homozygous or compound heterozygous mutations in a gene that encodes ganglioside-induced differentiation-associated protein-1 (GDAP1). GDAP1 is located on 8q21, and plays a major role in ganglioside differentiation and Schwann cell function, as well as regulates neuronal and axonal development. Case presentation: In this study, we recruited a consanguineous south Indian family with an affected patient, an unaffected sibling, and the mother. The patient was affected with progressive weakness in the lower and upper limbs, atrophy of small muscles of the foot and hands, club shaped hands, steppage gait, hoarseness, and decreased muscle tone. His nerve biopsy examination revealed peripheral nerve demyelination and nerve conduction testing confirmed a reduction in nerve activities, while MRI showed mild degenerative changes in the cervical spine. Further, targeted exome sequencing (TES) and copy number variation analysis were performed on the patient. TES identified a compound heterozygous mutation that includes a missense mutation and a 3’UTR mutation (NM_018972.4: c.413A > G:p.His138Arg; g.74488790C > A:c.*29C > A, respectively) in GDAP1. The missense change is not reported in available public databases, while the UTR variant is seen only in the South Asian population in gnomAD (allele frequency = 0.00002). Multiple in silico prediction tools show that the missense mutation is damaging. Subsequently, in silico protein modeling, phylogenetic conservation analysis, and the impact of the mutation on the canonical transcript have also been performed. The compound heterozygous mutation was confirmed in the patient by PCR-Sanger sequencing and was shown to segregate within the family. Conclusions: The combined results support the fact that these two mutations in GDAP1 link the genotype–phenotype correlation in the family. This will help the family in genetic testing, counseling, and early diagnosis. Our findings support expanded phenotypic characterization along with the genetic spectrum of GDAP1 mutations in CMT type4A in the Indian population. © The Author(s) 2025.
Modeling of human parkinson’s disease in fly
(Springer Singapore, 2019) Souradip Chatterjee; Pradeep Kumar Bhaskar; Ashim Mukherjee; Mousumi Mutsuddi
Years of in-depth research have contributed substantially to the understanding of the pathophysiology of Parkinson’s diseases (PD). However, many crucial questions related to the etiology of the disease remain unanswered, which compelled the need for developing more realistic and genetically malleable model systems for modeling the precise neuropathology of the disease in vivo. Ever-expanding genetic toolkit and conservation of implicated signaling pathways and neurological properties have prompted the use of Drosophila melanogaster (fly) as an instrumental model. Humanized fly models have aided in gaining insight into different cellular disturbances (protein aggregation and misfolding), mitochondrial deficits, and oxidative stress toward causation of Parkinson’s disease. The transgenic and humanized Drosophila model provides a decisive platform to assess the pathogenic properties of rare variants and open a window to analyze the cellular processes and signaling pathways that have been disrupted, which is ultimately manifested by the death of dopaminergic neurons in the brain of Parkinson-affected subjects. Apart from gaining molecular insight, toxin-induced models of Drosophila recapitulate multiple symptoms of environmental toxin-induced PD. Environmental toxin-induced models of Drosophila have proven to be an efficient means to study gene-environment interactions, which elevate susceptibility for Parkinsonism. Employment of Drosophila to scrutinize gene-environment interactions has led to the screening of many genetic risk factors. Additionally, the rapid development of genome manipulation technologies have paced up the development of more realistic models, which can precisely replicate all pathological features of the disease. This should be worthwhile to elucidate uncharted genetic and environmental risk factors, which are responsible for the complex pathogenesis associated with Parkinson’s disease. The ease of genetic manipulations that mimic symptoms of PD in Drosophila makes it one of the most favorite model organisms for analyzing the underlying cause of PD, the second most prevalent neurological disorder after Alzheimer’s disease. © Springer Nature Singapore Pte Ltd. 2019.
TP53 codon 72 polymorphism and the risk of glaucoma in a north Indian cohort: A genetic association study
(Taylor and Francis Ltd, 2018) Shashank Gupta; Souradip Chatterjee; Abhishek Chandra; Om Prakash Singh Maurya; Ravindra Nath Mishra; Ashim Mukherjee; Mousumi Mutsuddi
Background: The TP53 codon 72 Proline-Arginine polymorphism (TP53 P72R) is the most widely studied candidate among those evaluated for a putative association between impaired apoptosis and glaucoma. Considering the earlier findings about enhanced apoptotic potential by the Arg variant of TP53 P72R and the conflicting results about its association with glaucoma, we initiated a hospital-based case-control association study in a north Indian cohort to investigate the association of TP53 P72R with glaucoma. Materials and methods: We examined the status of TP53 P72R in 139 cases of primary open angle glaucoma (POAG) and in 111 cases of primary angle closure glaucoma (PACG) with respect to 218 controls using the polymerase chain reaction-restriction fragment length polymorphism method. Logistic regression analysis including age and gender as covariates was carried out to test the association of the polymorphism with overall glaucoma, POAG, and PACG cases. Results: We observed significant differences between the genotypic distributions of combined glaucoma cases and controls in the recessive model. POAG cases with respect to controls did not exhibit any significant differences in the genotypic distributions. In contrast, the genotypic distributions as per the additive and recessive models in PACG cases were significantly different from those in controls. The two models suggested an increased risk of PACG in the Arg homozygotes of the investigated cohort. Conclusions: Ours is the first study demonstrating the association of TP53 P72R with the risk of PACG. It emphasizes that apart from narrow anterior chamber angle, impaired apoptotic mechanisms could also be an important contributor toward PACG. © 2017 Taylor & Francis.
Variants in exon 2 of MED12 gene causes uterine leiomyoma's through over-expression of MMP-9 of ECM pathway
(Elsevier B.V., 2024) Vivek Pandey; Priyanka Jain; Souradip Chatterjee; Anjali Rani; Anima Tripathi; Pawan K. Dubey
Aims: To study the impact of Mediator complex subunit 12 (MED12) gene variants on the encoded protein's function and pathogenic relevance for genesis of uterine leiomyoma's (ULs). Methods: Mutational analysis in exon-2 of MED12 gene was performed by PCR amplification and DNA sequencing in 89 clinically diagnosed ULs tissues. Pathogenicity prediction of variation was performed by computational analysis. The functional effects of missense variation were done by quantity RT-PCR and western blot analysis. Result(s): Out of 89 samples, 40 (44.94%) had missense variation in 14 different CDS position of exon-2 of MED12 gene. Out of 40 missense variation, codon 44 had 25 (62.5%) looking as a hotspot region for mutation for ULs, because CDS position c130 and c131present at codon 44 that have necleotide change G>A, T, C at c130 and c131 have necleotide change G>A and C. We also find somenovel somatic mutations oncodon 36 (T > C), 38 (G>T) of exon-2 and 88 (G>C) of intron-2. No mutations were detected in uterine myometrium samples. Our computational analysis suggests that change in Med12c.131 G>A leads to single substitution of amino acid [Glycine (G) to Aspartate (D)] which has a pathogenic and lethal impact and may cause instability of MED12 protein. Further, analysis of extracellular matrix (ECM) component (MMP-2 & 9, COL4A2 and α-SMA) mRNA and protein expression levels in the set of ULs having MED12 mutation showed significantly higher expression of MMP-9 and α-SMA. Conclusion(s): The findings of present study suggest that missense variation in codon 44 of MED12 gene lead to the genesis of leiomyoma's through over-expression of MMP-9 of ECM pathway which could be therapeutically targeted for non-surgical management of ULs. © 2023 Elsevier B.V.
Whole exome sequencing identifies a novel splice-site mutation in IMPG2 gene causing Stargardt-like juvenile macular dystrophy in a north Indian family
(Elsevier B.V., 2022) Souradip Chatterjee; Shashank Gupta; Vidya Nair Chaudhry; Prashaant Chaudhry; Ashim Mukherjee; Mousumi Mutsuddi
We report on the genetic analysis of a north Indian family affected with Stargardt-like juvenile macular dystrophy. Considering an autosomal recessive inheritance of macular dystrophy in the recruited family, whole exome sequencing was employed in two affected siblings and their mother. We have identified a novel splice-site variant NC_000003.11(NM_016247.3):c.1239 + 1G > T, co-segregating in the affected siblings, in the Interphotoreceptor Matrix Proteoglycan 2 (IMPG2) gene. The identified variant is present immediately after exon 11, and is predicted to disrupt the wild-type donor splice-site of IMPG2 transcripts. We confirmed the splice-site changes in the IMPG2 transcripts using minigene functional assay. Although a number of studies on IMPG2 have demonstrated its involvement in retinitis pigmentosa and vitelliform macular dystrophy, this is the first report of a splice-site variant in IMPG2 that is responsible for Stargardt-like juvenile macular dystrophy. © 2022 Elsevier B.V.
Whole exome sequencing: Uncovering causal genetic variants for ocular diseases
(Academic Press, 2017) Shashank Gupta; Souradip Chatterjee; Ashim Mukherjee; Mousumi Mutsuddi
Identification of causal genetic defects for human diseases took a significant leap when the first generation DNA sequencing technologies enabled biologists extract sequence-based genetic information from living beings. However, these sequencing methods had unavoidable constraints of throughput, scalability, rapidity, and resolution. In this direction, next-generation sequencing (NGS) since the time of its advent has revolutionized the process of gene discovery for both monogenic and multifactorial genetic diseases. Among several variations of NGS, whole exome sequencing (WES) has emerged as a smart strategy that enables identification of disease causing variants present within the coding region of the human genome. The current review focuses primarily on the application of WES in identification of causal variants for ocular diseases. WES has successfully revealed pathogenic variants in a variety of ocular diseases such as retinal degenerations, refractive errors, lens diseases, corneal dystrophies, and developmental ocular defects. It has demonstrated immense potential for molecular diagnosis of genetic ocular diseases. WES has been extensively used in Mendelian and complex cases, familial and sporadic cases, simplex and multiplex cases, and syndromic and non-syndromic cases of ocular diseases. Although many such ocular diseases have been investigated using WES, reports indicate that it has been employed overwhelmingly for heterogeneous retinal degenerations. WES, within a short period of time, has proved to be a cost-effective and promising approach for understanding the genetic basis of ocular diseases. © 2017 Elsevier Ltd