De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Andreea Manole; Stephanie Efthymiou; Emer O'Connor; Marisa I. Mendes; Matthew Jennings; Reza Maroofian; Indran Davagnanam; Kshitij Mankad; Maria Rodriguez Lopez; Vincenzo Salpietro; Ricardo Harripaul; Lauren Badalato; Jagdeep Walia; Christopher S. Francklyn; Alkyoni Athanasiou-Fragkouli; Roisin Sullivan; Sonal Desai; Kristin Baranano; Faisal Zafar; Nuzhat Rana; Muhammed Ilyas; Alejandro Horga; Majdi Kara; Francesca Mattioli; Alice Goldenberg; Helen Griffin; Amelie Piton; Lindsay B. Henderson; Benyekhlef Kara; Ayca Dilruba Aslanger; Joost Raaphorst; Rolph Pfundt; Ruben Portier; Marwan Shinawi; Amelia Kirby; Katherine M. Christensen; Lu Wang; Rasim O. Rosti; Sohail A. Paracha; Muhammad T. Sarwar; Dagan Jenkins; Jawad Ahmed; Federico A. Santoni; Emmanuelle Ranza; Justyna Iwaszkiewicz; Cheryl Cytrynbaum; Rosanna Weksberg; Ingrid M. Wentzensen; Maria J. Guillen Sacoto; Yue Si; Aida Telegrafi; Marisa V. Andrews; Dustin Baldridge; Heinz Gabriel; Julia Mohr; Barbara Oehl-Jaschkowitz; Sylvain Debard; Bruno Senger; Frédéric Fischer; Conny van Ravenwaaij; Annemarie J.M. Fock; Servi J.C. Stevens; Jürg Bähler; Amina Nasar; John F. Mantovani; Adnan Manzur; Anna Sarkozy; Desirée E.C. Smith; Gajja S. Salomons; Zubair M. Ahmed; Shaikh Riazuddin; Saima Riazuddin; Muhammad A. Usmani; Annette Seibt; Muhammad Ansar; Stylianos E. Antonarakis; John B. Vincent; Muhammad Ayub; Mona Grimmel; Anne Marie Jelsig; Tina Duelund Hjortshøj; Helena Gásdal Karstensen; Marybeth Hummel; Tobias B. Haack; Yalda Jamshidi; Felix Distelmaier; Rita Horvath; Joseph G. Gleeson; Hubert Becker; Jean Louis Mandel; David A. Koolen; Henry Houlden; SYNAPS Study Group

doi:10.1016/j.ajhg.2020.06.016

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Andreea Manole, Stephanie Efthymiou, Emer O'Connor, Marisa I. Mendes, Matthew Jennings, Reza Maroofian, Indran Davagnanam, Kshitij Mankad, Maria Rodriguez Lopez, Vincenzo Salpietro, Ricardo Harripaul, Lauren Badalato, Jagdeep Walia, Christopher S. Francklyn, Alkyoni Athanasiou-Fragkouli, Roisin Sullivan, Sonal Desai, Kristin Baranano, Faisal Zafar, Nuzhat RanaMuhammed Ilyas, Alejandro Horga, Majdi Kara, Francesca Mattioli, Alice Goldenberg, Helen Griffin, Amelie Piton, Lindsay B. Henderson, Benyekhlef Kara, Ayca Dilruba Aslanger, Joost Raaphorst, Rolph Pfundt, Ruben Portier, Marwan Shinawi, Amelia Kirby, Katherine M. Christensen, Lu Wang, Rasim O. Rosti, Sohail A. Paracha, Muhammad T. Sarwar, Dagan Jenkins, Jawad Ahmed, Federico A. Santoni, Emmanuelle Ranza, Justyna Iwaszkiewicz, Cheryl Cytrynbaum, Rosanna Weksberg, Ingrid M. Wentzensen, Maria J. Guillen Sacoto, Yue Si, Aida Telegrafi, Marisa V. Andrews, Dustin Baldridge, Heinz Gabriel, Julia Mohr, Barbara Oehl-Jaschkowitz, Sylvain Debard, Bruno Senger, Frédéric Fischer, Conny van Ravenwaaij, Annemarie J.M. Fock, Servi J.C. Stevens, Jürg Bähler, Amina Nasar, John F. Mantovani, Adnan Manzur, Anna Sarkozy, Desirée E.C. Smith, Gajja S. Salomons, Zubair M. Ahmed, Shaikh Riazuddin, Saima Riazuddin, Muhammad A. Usmani, Annette Seibt, Muhammad Ansar, Stylianos E. Antonarakis, John B. Vincent, Muhammad Ayub, Mona Grimmel, Anne Marie Jelsig, Tina Duelund Hjortshøj, Helena Gásdal Karstensen, Marybeth Hummel, Tobias B. Haack, Yalda Jamshidi, Felix Distelmaier, Rita Horvath, Joseph G. Gleeson, Hubert Becker, Jean Louis Mandel, David A. Koolen, Henry Houlden^*, SYNAPS Study Group

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	311-324
Number of pages	14
Journal	American journal of human genetics
Volume	107
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2020.06.016
Publication status	Published - 6 Aug 2020

Access to Document

10.1016/j.ajhg.2020.06.016

Cite this

Manole, A., Efthymiou, S., O'Connor, E., Mendes, M. I., Jennings, M., Maroofian, R., Davagnanam, I., Mankad, K., Lopez, M. R., Salpietro, V., Harripaul, R., Badalato, L., Walia, J., Francklyn, C. S., Athanasiou-Fragkouli, A., Sullivan, R., Desai, S., Baranano, K., Zafar, F., ... SYNAPS Study Group (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. American journal of human genetics, 107(2), 311-324. https://doi.org/10.1016/j.ajhg.2020.06.016

@article{c3a406b1895d455792a7100a86fd9ac9,

title = "De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects",

abstract = "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.",

keywords = "aminoacyl-tRNA synthetase, developmental delay, epilepsy, neurodevelopment, neuropathy, next generation sequencing",

author = "Andreea Manole and Stephanie Efthymiou and Emer O'Connor and Mendes, {Marisa I.} and Matthew Jennings and Reza Maroofian and Indran Davagnanam and Kshitij Mankad and Lopez, {Maria Rodriguez} and Vincenzo Salpietro and Ricardo Harripaul and Lauren Badalato and Jagdeep Walia and Francklyn, {Christopher S.} and Alkyoni Athanasiou-Fragkouli and Roisin Sullivan and Sonal Desai and Kristin Baranano and Faisal Zafar and Nuzhat Rana and Muhammed Ilyas and Alejandro Horga and Majdi Kara and Francesca Mattioli and Alice Goldenberg and Helen Griffin and Amelie Piton and Henderson, {Lindsay B.} and Benyekhlef Kara and Aslanger, {Ayca Dilruba} and Joost Raaphorst and Rolph Pfundt and Ruben Portier and Marwan Shinawi and Amelia Kirby and Christensen, {Katherine M.} and Lu Wang and Rosti, {Rasim O.} and Paracha, {Sohail A.} and Sarwar, {Muhammad T.} and Dagan Jenkins and Jawad Ahmed and Santoni, {Federico A.} and Emmanuelle Ranza and Justyna Iwaszkiewicz and Cheryl Cytrynbaum and Rosanna Weksberg and Wentzensen, {Ingrid M.} and {Guillen Sacoto}, {Maria J.} and Yue Si and Aida Telegrafi and Andrews, {Marisa V.} and Dustin Baldridge and Heinz Gabriel and Julia Mohr and Barbara Oehl-Jaschkowitz and Sylvain Debard and Bruno Senger and Fr{\'e}d{\'e}ric Fischer and {van Ravenwaaij}, Conny and Fock, {Annemarie J.M.} and Stevens, {Servi J.C.} and J{\"u}rg B{\"a}hler and Amina Nasar and Mantovani, {John F.} and Adnan Manzur and Anna Sarkozy and Smith, {Desir{\'e}e E.C.} and Salomons, {Gajja S.} and Ahmed, {Zubair M.} and Shaikh Riazuddin and Saima Riazuddin and Usmani, {Muhammad A.} and Annette Seibt and Muhammad Ansar and Antonarakis, {Stylianos E.} and Vincent, {John B.} and Muhammad Ayub and Mona Grimmel and Jelsig, {Anne Marie} and Hjortsh{\o}j, {Tina Duelund} and Karstensen, {Helena G{\'a}sdal} and Marybeth Hummel and Haack, {Tobias B.} and Yalda Jamshidi and Felix Distelmaier and Rita Horvath and Gleeson, {Joseph G.} and Hubert Becker and Mandel, {Jean Louis} and Koolen, {David A.} and Henry Houlden and {SYNAPS Study Group}",

year = "2020",

month = aug,

day = "6",

doi = "10.1016/j.ajhg.2020.06.016",

language = "English",

volume = "107",

pages = "311--324",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "2",

}

Manole, A, Efthymiou, S, O'Connor, E, Mendes, MI, Jennings, M, Maroofian, R, Davagnanam, I, Mankad, K, Lopez, MR, Salpietro, V, Harripaul, R, Badalato, L, Walia, J, Francklyn, CS, Athanasiou-Fragkouli, A, Sullivan, R, Desai, S, Baranano, K, Zafar, F, Rana, N, Ilyas, M, Horga, A, Kara, M, Mattioli, F, Goldenberg, A, Griffin, H, Piton, A, Henderson, LB, Kara, B, Aslanger, AD, Raaphorst, J, Pfundt, R, Portier, R, Shinawi, M, Kirby, A, Christensen, KM, Wang, L, Rosti, RO, Paracha, SA, Sarwar, MT, Jenkins, D, Ahmed, J, Santoni, FA, Ranza, E, Iwaszkiewicz, J, Cytrynbaum, C, Weksberg, R, Wentzensen, IM, Guillen Sacoto, MJ, Si, Y, Telegrafi, A, Andrews, MV, Baldridge, D, Gabriel, H, Mohr, J, Oehl-Jaschkowitz, B, Debard, S, Senger, B, Fischer, F, van Ravenwaaij, C, Fock, AJM, Stevens, SJC, Bähler, J, Nasar, A, Mantovani, JF, Manzur, A, Sarkozy, A, Smith, DEC , Salomons, GS, Ahmed, ZM, Riazuddin, S, Riazuddin, S, Usmani, MA, Seibt, A, Ansar, M, Antonarakis, SE, Vincent, JB, Ayub, M, Grimmel, M, Jelsig, AM, Hjortshøj, TD, Karstensen, HG, Hummel, M, Haack, TB, Jamshidi, Y, Distelmaier, F, Horvath, R, Gleeson, JG, Becker, H, Mandel, JL, Koolen, DA, Houlden, H & SYNAPS Study Group 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', American journal of human genetics, vol. 107, no. 2, pp. 311-324. https://doi.org/10.1016/j.ajhg.2020.06.016

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 et al.

In: American journal of human genetics, Vol. 107, No. 2, 06.08.2020, p. 311-324.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

AU - Manole, Andreea

AU - Efthymiou, Stephanie

AU - O'Connor, Emer

AU - Mendes, Marisa I.

AU - Jennings, Matthew

AU - Maroofian, Reza

AU - Davagnanam, Indran

AU - Mankad, Kshitij

AU - Lopez, Maria Rodriguez

AU - Salpietro, Vincenzo

AU - Harripaul, Ricardo

AU - Badalato, Lauren

AU - Walia, Jagdeep

AU - Francklyn, Christopher S.

AU - Athanasiou-Fragkouli, Alkyoni

AU - Sullivan, Roisin

AU - Desai, Sonal

AU - Baranano, Kristin

AU - Zafar, Faisal

AU - Rana, Nuzhat

AU - Ilyas, Muhammed

AU - Horga, Alejandro

AU - Kara, Majdi

AU - Mattioli, Francesca

AU - Goldenberg, Alice

AU - Griffin, Helen

AU - Piton, Amelie

AU - Henderson, Lindsay B.

AU - Kara, Benyekhlef

AU - Aslanger, Ayca Dilruba

AU - Raaphorst, Joost

AU - Pfundt, Rolph

AU - Portier, Ruben

AU - Shinawi, Marwan

AU - Kirby, Amelia

AU - Christensen, Katherine M.

AU - Wang, Lu

AU - Rosti, Rasim O.

AU - Paracha, Sohail A.

AU - Sarwar, Muhammad T.

AU - Jenkins, Dagan

AU - Ahmed, Jawad

AU - Santoni, Federico A.

AU - Ranza, Emmanuelle

AU - Iwaszkiewicz, Justyna

AU - Cytrynbaum, Cheryl

AU - Weksberg, Rosanna

AU - Wentzensen, Ingrid M.

AU - Guillen Sacoto, Maria J.

AU - Si, Yue

AU - Telegrafi, Aida

AU - Andrews, Marisa V.

AU - Baldridge, Dustin

AU - Gabriel, Heinz

AU - Mohr, Julia

AU - Oehl-Jaschkowitz, Barbara

AU - Debard, Sylvain

AU - Senger, Bruno

AU - Fischer, Frédéric

AU - van Ravenwaaij, Conny

AU - Fock, Annemarie J.M.

AU - Stevens, Servi J.C.

AU - Bähler, Jürg

AU - Nasar, Amina

AU - Mantovani, John F.

AU - Manzur, Adnan

AU - Sarkozy, Anna

AU - Smith, Desirée E.C.

AU - Salomons, Gajja S.

AU - Ahmed, Zubair M.

AU - Riazuddin, Shaikh

AU - Riazuddin, Saima

AU - Usmani, Muhammad A.

AU - Seibt, Annette

AU - Ansar, Muhammad

AU - Antonarakis, Stylianos E.

AU - Vincent, John B.

AU - Ayub, Muhammad

AU - Grimmel, Mona

AU - Jelsig, Anne Marie

AU - Hjortshøj, Tina Duelund

AU - Karstensen, Helena Gásdal

AU - Hummel, Marybeth

AU - Haack, Tobias B.

AU - Jamshidi, Yalda

AU - Distelmaier, Felix

AU - Horvath, Rita

AU - Gleeson, Joseph G.

AU - Becker, Hubert

AU - Mandel, Jean Louis

AU - Koolen, David A.

AU - Houlden, Henry

AU - SYNAPS Study Group

PY - 2020/8/6

Y1 - 2020/8/6

N2 - 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.

AB - 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.

KW - aminoacyl-tRNA synthetase

KW - developmental delay

KW - epilepsy

KW - neurodevelopment

KW - neuropathy

KW - next generation sequencing

UR - http://www.scopus.com/inward/record.url?scp=85088934445&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2020.06.016

DO - 10.1016/j.ajhg.2020.06.016

M3 - Article

C2 - 32738225

AN - SCOPUS:85088934445

VL - 107

SP - 311

EP - 324

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

IS - 2

ER -

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Abstract

Access to Document

Other files and links

Cite this