Медицинская библиотека · American journal of human genetics · 2020
De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.
Manole Andreea, Efthymiou Stephanie, O'Connor Emer, Mendes Marisa I, Jennings Matthew, Maroofian Reza, Davagnanam Indran, Mankad Kshitij, Lopez Maria Rodriguez, Salpietro Vincenzo, Harripaul Ricardo, Badalato Lauren, Walia Jagdeep, Francklyn Christopher S, Athanasiou-Fragkouli Alkyoni, Sullivan Roisin, Desai Sonal, Baranano Kristin, Zafar Faisal, Rana Nuzhat, Ilyas Muhammed, Horga Alejandro, Kara Majdi, Mattioli Francesca, Goldenberg Alice, Griffin Helen, Piton Amelie, Henderson Lindsay B, Kara Benyekhlef, Aslanger Ayca Dilruba, Raaphorst Joost, Pfundt Rolph, Portier Ruben, Shinawi Marwan, Kirby Amelia, Christensen Katherine M, Wang Lu, Rosti Rasim O, Paracha Sohail A, Sarwar Muhammad T, Jenkins Dagan, SYNAPS Study Group, Ahmed Jawad, Santoni Federico A, Ranza Emmanuelle, Iwaszkiewicz Justyna, Cytrynbaum Cheryl, Weksberg Rosanna, Wentzensen Ingrid M, Guillen Sacoto Maria J, Si Yue, Telegrafi Aida, Andrews Marisa V, Baldridge Dustin, Gabriel Heinz, Mohr Julia, Oehl-Jaschkowitz Barbara, Debard Sylvain, Senger Bruno, Fischer Frédéric, van Ravenwaaij Conny, Fock Annemarie J M, Stevens Servi J C, Bähler Jürg, Nasar Amina, Mantovani John F, Manzur Adnan, Sarkozy Anna, Smith Desirée E C, Salomons Gajja S, Ahmed Zubair M, Riazuddin Shaikh, Riazuddin Saima, Usmani Muhammad A, Seibt Annette, Ansar Muhammad, Antonarakis Stylianos E, Vincent John B, Ayub Muhammad, Grimmel Mona, Jelsig Anne Marie, Hjortshøj Tina Duelund, Karstensen Helena Gásdal, Hummel Marybeth, Haack Tobias B, Jamshidi Yalda, Distelmaier Felix, Horvath Rita, Gleeson Joseph G, Becker Hubert, Mandel Jean-Louis, Koolen David A, Houlden Henry
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Аннотация
Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.
Для цитирования: Manole Andreea, Efthymiou Stephanie, O'Connor Emer, Mendes Marisa I, Jennings Matthew, Maroofian Reza, Davagnanam Indran, Mankad Kshitij, Lopez Maria Rodriguez, Salpietro Vincenzo, Harripaul Ricardo, Badalato Lauren, Walia Jagdeep, Francklyn Christopher S, Athanasiou-Fragkouli Alkyoni, Sullivan Roisin, Desai Sonal, Baranano Kristin, Zafar Faisal, Rana Nuzhat, Ilyas Muhammed, Horga Alejandro, Kara Majdi, Mattioli Francesca, Goldenberg Alice, Griffin Helen, Piton Amelie, Henderson Lindsay B, Kara Benyekhlef, Aslanger Ayca Dilruba, Raaphorst Joost, Pfundt Rolph, Portier Ruben, Shinawi Marwan, Kirby Amelia, Christensen Katherine M, Wang Lu, Rosti Rasim O, Paracha Sohail A, Sarwar Muhammad T, Jenkins Dagan, SYNAPS Study Group, Ahmed Jawad, Santoni Federico A, Ranza Emmanuelle, Iwaszkiewicz Justyna, Cytrynbaum Cheryl, Weksberg Rosanna, Wentzensen Ingrid M, Guillen Sacoto Maria J, Si Yue, Telegrafi Aida, Andrews Marisa V, Baldridge Dustin, Gabriel Heinz, Mohr Julia, Oehl-Jaschkowitz Barbara, Debard Sylvain, Senger Bruno, Fischer Frédéric, van Ravenwaaij Conny, Fock Annemarie J M, Stevens Servi J C, Bähler Jürg, Nasar Amina, Mantovani John F, Manzur Adnan, Sarkozy Anna, Smith Desirée E C, Salomons Gajja S, Ahmed Zubair M, Riazuddin Shaikh, Riazuddin Saima, Usmani Muhammad A, Seibt Annette, Ansar Muhammad, Antonarakis Stylianos E, Vincent John B, Ayub Muhammad, Grimmel Mona, Jelsig Anne Marie, Hjortshøj Tina Duelund, Karstensen Helena Gásdal, Hummel Marybeth, Haack Tobias B, Jamshidi Yalda, Distelmaier Felix, Horvath Rita, Gleeson Joseph G, Becker Hubert, Mandel Jean-Louis, Koolen David A, Houlden Henry. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.. American journal of human genetics. 2020. DOI: 10.1016/j.ajhg.2020.06.016.
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