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Scientific program

September 29, 2021    ,

6th Webinar on Human Genetics

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Speakers

Ritu Dixit
2

Ritu Dixit

Banaras Hindu University, India India

Title: Genetic Disorders

Abstract:

Mutations of GATA4, a cardiogenic transcription factor, cause cardiac septal defects and cardiomyopathy in humans. Many of these interacting partners are well recognized, These variants involving highly conserved residues of protein may affect protein-protein or protein-DNA interactions, leading to gene regulatory network dysregulation and thereby causing human disease. Many of the interacting partners and downstream effectors have already been identified, however their cardiac specific downstream genes are still a mystery. Here we aimed to analyze the genome wide molecular effects of a novel GATA4 transactivation domain (TAD) variant (p.Ala8Asp). The genome-wide expression profile of the affected genes were compared between wildtype and mutant protein using RNA sequencing. Western blotting, dual luciferase promoter assay, EMSA and immunofluorescence was done to depict the effect of mutation on expression, transcriptional activity, DNA binding affinity and cellular localisation of GATA4 respectively. Total RNA-sequencing of transiently transfected P19 cells expressing wild-type and mutant proteins was performed. The novel variant, p.Ala8Asp was observed to be significantly associated with CHD in our patient cohort and in vitro studies revealed severe functional deficits. Transiently transfected P19 cells with p.Ala8Asp construct exhibited over-expression concomitantly enhancing the activation of cardiac specific Nppa and Actc1 promoters. Mutant protein depicted reduced DNA binding affinity in EMSA. Total transcriptome analysis of p.A8D vs WT showed 430 differentially expressed genes (DEGs), 280 of them were downregulated and 150 were upregulated. These genes were enriched in different biological processes including cardiac development (n=43 genes). Twelve of these genes were identified as direct targets of GATA4. SRF responsive genes (n=29) and MEF2C target genes (n=16) were also observed to be differentially regulated in response to GATA4 mutant reflecting the obligatory role of GATA4 in regulating the expression of these genes.

Biography:

Ritu Dixit did her Ph.D in cardiovascular genetics from Department of Zoology, Banaras Hindu University,  India. She holds a M.Sc in Biotechnology with outstanding performance including merit scholarship (2008-2010) and Junior Research Fellowship (2011-2014) from Department of Biotechnology, Ministry of Science and Technology, Government of India. She has been awarded travel grants (2016) from Indian Council of Medical Research (ICMR) and Department of Science and Technology (DST), New Delhi, India for attending international conferences. She was also awarded with Senior Research Fellowship from ICMR in 2014. She has 8 research articles in peer reviewed journals and 2 book chapters to her credit. She is currently working as a postdoctoral fellow at Brien Holden Eye Research Centre, LVPEI, Hyderabad, India. Her primary research interest is deciphering the molecular genetic basis of human diseases using cutting edge technologies. 

Developmental Genes
2

Developmental Genes

UK

Title: Developmental Genetics

E-Poster

Human Genetics
1

Human Genetics

UK

Title: Human Genetics

Useful Links

News

New resource to advance genomics-driven precision medicine

2021-09-02 - 2021-09

By analysing genomic data from more than 30,000 people, an international team has revealed thousands of new regulatory regions that control disease-linked genes -- a resource that is now available to researchers worldwide. The findings, co-led by the Garvan Institute of Medical Research and published today in Nature Genetics, are a significant step forward for genomics-driven precision medicine and could help identify markers that reveal which patients will benefit most from which treatment. "In this study we have provided an entirely new view of genetic regulation by uncovering an in-depth picture of how genes and disease are linked. It is the most comprehensive analysis of how human genetic variation affects gene expression to date," says co-senior author Associate Professor Joseph Powell, Director of the Garvan-Weizmann Centre for Cellular Genomics and Deputy Director of the UNSW Cellular Genomics Futures Institute. "Our discovery provides researchers an entirely new perspective on their genes of interest, and will help prioritise genes that may be more relevant for therapeutic intervention. It could also lead us to better markers for tracking disease progression and the efficacy of medicines," says co-senior author Professor Lude Franke from the University Medical Centre Groningen, Netherlands.

New, one-stop method developed to avoid de novo genetic disease in embryos

2021-08-31 - 2021-08

De novo variants (DNVs), genetic mutations that were not previously identifiable in the family history of one of two prospective parents, may cause disease in any children they have. Where a disease-causing DNV is present in one parent, the risk of passing it to a child can be as high as 50%, and being able to identify healthy embryos for transfer to avoid an affected pregnancy is clearly a high priority. To achieve this goal, identification of the group of genes inherited from one parent (the haplotype) that is linked with the mutation is necessary to transfer only healthy embryos. Until now this has been a difficult process and can often involve multiple embryo biopsies, which in themselves carry a risk. But a group of Belgian researchers has developed a new, one-stop method using DNA from the parents of the affected prospective parent (the embryo's/child's grandparents). They will present their findings to the annual conference of the European Society of Human Genetics today (Tuesday). Dr Eftychia Dimitriadou, Head of the Reproductive Genetics Unit at the Centre for Human Genetics, Leuven University Hospital, Leuven, Belgium, and colleagues recruited 22 couples where one of the partners carried a DNV mutation causing a Mendelian disorder. A Mendelian disorder is normally, but not always, caused by alterations in a single gene. Current practice for pre-implantation genetic testing (PGT) embryo selection for such couples is complicated, says Dr Dimitriadou. "It involves targeting a specific gene, and therefore important genome-wide information is missing."

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