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

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@article{d10edc071944420fab1b6d33ee77b3ad,

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 = "Alleles, Amino Acyl-tRNA Synthetases/genetics, Aspartate-tRNA Ligase/genetics, Cell Line, Female, Gain of Function Mutation/genetics, Genetic Predisposition to Disease/genetics, Humans, Loss of Function Mutation/genetics, Male, Neurodevelopmental Disorders/genetics, Pedigree, RNA, Transfer/genetics, RNA, Transfer, Amino Acyl/genetics, Stem Cells/physiology",

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 Jelsig, {Anne Marie} and Karstensen, {Helena G{\'a}sdal} and {SYNAPS Study Group}",

note = "Copyright {\textcopyright} 2020. Published by Elsevier Inc.",

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",

}

RIS

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 - Jelsig, Anne Marie

AU - Karstensen, Helena Gásdal

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 - Alleles

KW - Amino Acyl-tRNA Synthetases/genetics

KW - Aspartate-tRNA Ligase/genetics

KW - Cell Line

KW - Female

KW - Gain of Function Mutation/genetics

KW - Genetic Predisposition to Disease/genetics

KW - Humans

KW - Loss of Function Mutation/genetics

KW - Male

KW - Neurodevelopmental Disorders/genetics

KW - Pedigree

KW - RNA, Transfer/genetics

KW - RNA, Transfer, Amino Acyl/genetics

KW - Stem Cells/physiology

U2 - 10.1016/j.ajhg.2020.06.016

DO - 10.1016/j.ajhg.2020.06.016

M3 - Journal article

C2 - 32738225

VL - 107

SP - 311

EP - 324

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -

ID: 61319109

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

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