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Clinical and genetic spectrum of Ataxia Telangiectasia Tunisian patients: Bioinformatic analysis unveil mechanisms of ATM variants pathogenicity.
Jenni, Rim; Klaa, Hedia; Khamessi, Oussema; Chikhaoui, Asma; Najjar, Dorra; Ghedira, Kais; Kraoua, Ichraf; Turki, Ilhem; Yacoub-Youssef, Houda.
Afiliación
  • Jenni R; Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, University Tunis El Manar, Tunis 1002, Tunisia. Electronic address: rim.jenni19@gmail.com.
  • Klaa H; LR18SP04 and Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia. Electronic address: hedia.klaa@fmt.utm.tn.
  • Khamessi O; Laboratory of Bioinformatics, Biomathematics and Biostatistics (BIMS), Institut Pasteur de Tunis (IPT), University of Tunis El Manar, Tunis, Tunisia; Institut de Biotechnologie de Sidi Thabet, Université de la Manouba, Ariana BP-66, Manouba 2010, Tunisia. Electronic address: oussama.khamassi@pasteur
  • Chikhaoui A; Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, University Tunis El Manar, Tunis 1002, Tunisia. Electronic address: asma.chikhaoui@pasteur.utm.tn.
  • Najjar D; Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, University Tunis El Manar, Tunis 1002, Tunisia. Electronic address: dorra.najjar@pasteur.utm.tn.
  • Ghedira K; Laboratory of Bioinformatics, Biomathematics and Biostatistics (BIMS), Institut Pasteur de Tunis (IPT), University of Tunis El Manar, Tunis, Tunisia. Electronic address: kaies.ghedira@pasteur.tn.
  • Kraoua I; LR18SP04 and Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia. Electronic address: ichraf.kraoua@fmt.utm.tn.
  • Turki I; LR18SP04 and Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007 Tunis, Tunisia. Electronic address: ilhem.byt@fmt.utm.tn.
  • Yacoub-Youssef H; Laboratory of Biomedical Genomics and Oncogenetics (LR16IPT05), Institut Pasteur de Tunis, University Tunis El Manar, Tunis 1002, Tunisia. Electronic address: houda.yacoub@pasteur.utm.tn.
Int J Biol Macromol ; 278(Pt 1): 134444, 2024 Oct.
Article en En | MEDLINE | ID: mdl-39098699
ABSTRACT
Ataxia Telangiectasia (AT) is a rare multisystemic neurodegenerative disease caused by biallelic mutations in the ATM gene. Few clinical studies on AT disease have been conducted in Tunisia, however, the mutational landscape is still undefined. Our aim is to determine the clinical and genetic spectrum of AT Tunisian patients and to explore the potential underlying mechanism of variant pathogenicity. Sanger sequencing was performed for nine AT patients. A comprehensive computational analysis was conducted to evaluate the possible pathogenic effect of ATM identified variants. Genetic screening of ATM gene has identified nine different variants from which six have not been previously reported. In silico analysis has predicted a pathogenic effect of identified mutations. This was corroborated by a structural bioinformatics study based on molecular modeling and docking for novel missense mutations. Our findings suggest a profound impact of identified mutations not only on the ATM protein stability, but also on the ATM-ligand interactions. Our study characterizes the mutational landscape of AT Tunisian patients which will allow to set up genetic counseling and prenatal diagnosis for families at risk and expand the spectrum of ATM variants worldwide. Furthermore, understanding the mechanism that underpin variant pathogenicity could provide further insights into disease pathogenesis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia Telangiectasia / Biología Computacional / Proteínas de la Ataxia Telangiectasia Mutada Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Male País/Región como asunto: Africa Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia Telangiectasia / Biología Computacional / Proteínas de la Ataxia Telangiectasia Mutada Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Male País/Región como asunto: Africa Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article Pais de publicación: Países Bajos