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Hypohidrotic ectodermal dysplasia (HED) is a rare genetic disorder caused by mutational inactivation of a developmental pathway responsible for generation of tissues of ectodermal origin. The X‐linked form accounts for the majority of HED cases and is caused by Ectodysplasin (EDA) pathogenic variants. We performed a combined analysis of 29 X‐linked hypohidrotic ectodermal dysplasia (XLHED) families (including 12 from our previous studies). In addition to the classical triad of symptoms including loss (or reduction) of ectodermal structures, such as hair, teeth, and sweat glands, we detected additional HED‐related clinical features including facial dysmorphism and hyperpigmentation in several patients. Interestingly, global developmental delay was identified as an unusual clinical symptom in many patients. More importantly, we identified 22 causal pathogenic variants that included 15 missense, four small in‐dels, and one nonsense, splice site, and large deletion each. Interestingly, we detected 12 unique (India‐specific) pathogenic variants. Of the 29 XLHED families analyzed, 11 (38%) harbored pathogenic variant localized to the furin cleavage site. A comparison with HGMD revealed significant differences in the frequency of missense pathogenic variants; involvement of specific exons and/or protein domains and transition/transversion ratios. A significantly higher proportion of missense pathogenic variants (33%) localized to the EDA furin cleavage when compared to HGMD (7%), of which p.R155C, p.R156C, and p.R156H were detected in three families each. Therefore, the first comprehensive analysis of XLHED from India has revealed several unique features including unusual clinical symptoms and high frequency of furin cleavage site pathogenic variants. [ABSTRACT FROM AUTHOR]

The ectodermal dysplasias (EDs) are a heterogeneous group of inherited, developmental disorders characterized by alterations in two or more ectodermal structures including the hair, teeth, nails and sweat glands. Currently, more than 200 types of ectodermal dysplasias have been described. Anhidrotic or hypohidrotic ectodermal dysplasia (AED/HED), the most common ED, is characterized by three cardinal features: hypotrichosis, hypohidrosis and hypodontia. We review the genetic and pathogenetic mechanisms of AED/HED and report on the management of clinical manifestations driven by embryology, anatomy and physiology. [ABSTRACT FROM AUTHOR]

Cancer is caused by malfunctioning of genes that normally regulate cardinal processes including various nuclear functions, cell division and survival, cell surface to nucleus signaling cascades, etc. Cancer associated genes are often classified as oncogenes (OCGs) or tumor suppressor genes (TSGs) depending on whether they promote or suppress tumorigenesis, respectively. Such strict classification of cancer genes may however be an over-simplification. Several studies have highlighted a dual role for cancer genes, often impacting the same facet of tumorigenesis. Knowledge of a possible dichotomy of a cancer gene (particularly an OCG) is imperative when evaluating its possible utility as a therapeutic target. Though previous studies have extensively evaluated specific examples of cancer genes exhibiting a dual nature, efforts to unravel the molecular basis for such contrasting functions have been fewer. The current review is an attempt to delineate molecular events underlying the functional dichotomy of cancer genes at the DNA (mutations, gene fusions, etc.), RNA (alternative splicing, regulation through non-coding RNAs, etc.) and protein (isoforms, mis-localisation, post-translational modifications, proteolytic cleavage, etc.) levels. • Cancer genes may display a dual nature exhibiting oncogenic as well as tumor suppressor functions. • This dichotomy can manifest at DNA, RNA or protein level. • The dual nature significantly impacts development of targeted therapies. [ABSTRACT FROM AUTHOR]

Purpose: The tumor suppressor p53 is known to be inactivated frequently in various cancers. In addition, germline polymorphisms in TP53 are known to affect protein function and influence risk of developing different types of cancers. In this study, we analyzed the association of TP53 Pro72Arg polymorphism with squamous cell carcinoma of oral tongue (SCCOT) and esophagus (ESCC) in India. Methods: We assessed the distribution of TP53 Pro72Arg polymorphism in one hundred and fifteen and eighty two SCCOT and ESCC patients, respectively, with respect to one hundred and ten healthy controls from the same population. In addition, we analyzed association of the polymorphism with several clinico-pathological and molecular parameters. Results: Pro72 allele was significantly enriched in SCCOT patients compared to the healthy control group but neither allele was enriched in ESCC. Interestingly, Pro72 allele was preferentially mutated in ESCC which was confirmed by analysis of samples heterozygous for Pro72Arg. Conclusions: Our study revealed the association of Pro72 allele with SCCOT suggesting the effect of this polymorphism on SCCOT risk. Preferential mutation of Pro72 allele exclusively in ESCC indicates the need for further studies to understand the tissue specific effect of p53 polymorphism. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflicts of interest The authors declare no conflicts of interest.

Despite seminal advances towards understanding the infection mechanism of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), it continues to cause significant morbidity and mortality worldwide. Though mass immunization programmes have been implemented in several countries, the viral transmission cycle has shown a continuous progression in the form of multiple waves. A constant change in the frequencies of dominant viral lineages, arising from the accumulation of nucleotide variations (NVs) through favourable selection, is understandably expected to be a major determinant of disease severity and possible vaccine escape. Indeed, worldwide efforts have been initiated to identify specific virus lineage(s) and/or NVs that may cause a severe clinical presentation or facilitate vaccination breakthrough. Since host genetics is expected to play a major role in shaping virus evolution, it is imperative to study the role of genome-wide SARS-CoV-2 NVs across various populations. In the current study, we analysed the whole genome sequence of 3543 SARS-CoV-2-infected samples obtained from the state of Telangana, India (including 210 from our previous study), collected over an extended period from April 2020 to October 2021. We present a unique perspective on the evolution of prevalent virus lineages and NVs during this period. We also highlight the presence of specific NVs likely to be associated favourably with samples classified as vaccination breakthroughs. Finally, we report genome-wide intra-host variations at novel genomic positions. The results presented here provide critical insights into virus evolution over an extended period and pave the way to rigorously investigate the role of specific NVs in vaccination breakthroughs., Competing Interests: The author(s) declare that there are no conflicts of interest., (© 2023 The Authors.)

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 has rapidly turned into a pandemic, infecting millions and causing 1 157 509 (as of 27 October 2020) deaths across the globe. In addition to studying the mode of transmission and evasion of host immune system, analysing the viral mutational landscape constitutes an area under active research. The latter is expected to impart knowledge on the emergence of different clades, subclades, viral protein functions and protein-protein and protein-RNA interactions during replication/transcription cycle of virus and response to host immune checkpoints. In this study, we have attempted to bring forth the viral genomic variants defining the major clade(s) as identified from samples collected from the state of Telangana, India. We further report a comprehensive draft of all genomic variations (including unique mutations) present in SARS-CoV-2 strain in the state of Telangana. Our results reveal the presence of two mutually exclusive subgroups defined by specific variants within the dominant clade present in the population. This work attempts to bridge the critical gap regarding the genomic landscape and associate mutations in SARS-CoV-2 from a highly infected southern region of India, which was lacking to date.

The ARID1B (BAF250b) subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. We employed in silico prediction, intracellular fluorescence and cellular fractionation-based subcellular localization analyses to identify the ARID1B nuclear localization signal (NLS). A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised in its canonical transcription activation and tumor suppressive functions, as expected. Surprisingly however, cytoplasmic localization appeared to induce a gain of oncogenic function for ARID1B, as evidenced from several cell line- and mouse xenograft-based assays. Mechanistically, cytoplasm-localized ARID1B could bind c-RAF (RAF1) and PPP1CA causing stimulation of RAF-ERK signaling and β-catenin (CTNNB1) transcription activity. ARID1B harboring NLS mutations derived from tumor samples also exhibited aberrant cytoplasmic localization and acquired a neo-morphic oncogenic function via activation of RAF-ERK signaling. Furthermore, immunohistochemistry on a tissue microarray revealed significant correlation of ARID1B cytoplasmic localization with increased levels of active forms of ERK1 and ERK2 (also known as MAPK3 and MAPK1) and of β-catenin, as well as with advanced tumor stage and lymph node positivity in human primary pancreatic tumor tissues. ARID1B therefore promotes oncogenesis through cytoplasm-based gain-of-function mechanisms in addition to dysregulation in the nucleus.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Background: Squamous cell carcinoma of tongue (SCCT) is expected to harbor unique clinico-pathological and molecular genetic features since a significant proportion of patients are young and exhibit no association with tobacco or alcohol., Methods: We determined P53, epidermal growth factor receptor, microsatellite instability, human papilloma virus infection and loss of heterozygosity status at several tumor suppressor loci in one hundred and twenty one oral SCCT (SSCOT) samples and analyzed their association with clinico-pathological features and patient survival., Results: Our results revealed a significantly higher incidence of p53 nuclear stabilization in early (as against late) onset SCCOT. FHIT loss was significantly associated with p53 nuclear stabilization and the association was stronger in patients with no history of tobacco use. Samples harboring mutation in p53 DNA binding domain or exhibiting p53 nuclear stabilization, were significantly associated with poor survival., Conclusion: Our study has therefore identified distinct features in SCCOT tumorigenesis with respect to age and tobacco exposure and revealed possible prognostic utility of p53.