A Novel NRAS Variant Near the Splice Junction in Moroccan Childhood Acute Lymphoblastic Leukemia: A Molecular Dynamics Study.

Autor: Skhoun H; Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco.; Laboratory of Human Pathologies Biology and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco., El Fessikh M; Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco.; Laboratory of Human Pathologies Biology and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco., Khattab M; Pediatric Hematology and Oncology Center, Children's Hospital, Rabat, Morocco.; Centre of Childhood Care and Prevention, Cheikh Zaid International University Hospital, Rabat, Morocco., Mchich B; Unité de Biologie Fonctionnelle Et Adaptative, Université Paris Cité, CNRS, INSERM, Paris, France., Agadr A; Department of Pediatrics, Military Hospital Mohammed V, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco., Abilkassem R; Department of Pediatrics, Military Hospital Mohammed V, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco., Dakka N; Laboratory of Human Pathologies Biology and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University, Rabat, Morocco., Flatters D; Unité de Biologie Fonctionnelle Et Adaptative, Université Paris Cité, CNRS, INSERM, Paris, France., Camproux AC; Unité de Biologie Fonctionnelle Et Adaptative, Université Paris Cité, CNRS, INSERM, Paris, France., Ouzzif Z; Laboratories Pole, Military Hospital Mohammed V, Rabat, Morocco., El Baghdadi J; Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco. baghdadijamila@yahoo.fr.; Laboratories Pole, Military Hospital Mohammed V, Rabat, Morocco. baghdadijamila@yahoo.fr.
Jazyk: angličtina
Zdroj: Biochemical genetics [Biochem Genet] 2024 Nov 08. Date of Electronic Publication: 2024 Nov 08.
DOI: 10.1007/s10528-024-10968-2
Abstrakt: The RAS genes are importantly implicated in oncogenesis and are frequently mutated in childhood acute lymphoblastic leukemia. This study is the first to our knowledge, to determine the mutational status of NRAS and KRAS genes in Moroccan pediatric acute lymphoblastic leukemia (ALL). Polymerase chain reaction and Sanger sequencing were performed for 45 ALL samples to explore the coding exons. The functional effect of the mutation was evaluated using in silico prediction tools and molecular modeling. We identified a novel variant c.290 G > C p.Arg97Thr within NRAS gene in a patient with T-ALL, which is a rare missense point mutation affecting the last base of exon 3. Analyses revealed that p.Arg97Thr impairs the adjacent splice site efficiency. Moreover, it leads to structural modifications at local and global levels of the protein through the loss of hydrogen bonds. Additionally, the molecular dynamics (MD) simulation showed that it slightly increases the stability of NRAS protein by locally decreasing the flexibility of the mutated region. No variant was detected within KRAS gene. R97 at NRAS gene is an overlapping splice site residue. Our findings suggest that the NRAS p.Arg97Thr variant may disrupt the splicing machinery and functions of the protein, thus playing a vital role in leukemogenesis. In addition, the highly druggable pocket may possibly be studied for its therapeutic implications.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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