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3 results on '"Fock, AJM"'

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

Author

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, SYNAPS Study Group, 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, 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, J-L, Koolen, DA, and Houlden, H

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.

Published
2020

2. Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.

Author

Donkervoort S, Mohassel P, Laugwitz L, Zaki MS, Kamsteeg EJ, Maroofian R, Chao KR, Verschuuren-Bemelmans CC, Horber V, Fock AJM, McCarty RM, Jain MS, Biancavilla V, McMacken G, Nalls M, Voermans NC, Elbendary HM, Snyder M, Cai C, Lehky TJ, Stanley V, Iannaccone ST, Foley AR, Lochmüller H, Gleeson J, Houlden H, Haack TB, Horvath R, and Bönnemann CG

Subjects
Adolescent, Child, Child, Preschool, Female, Humans, Male, Muscle Hypotonia complications, Muscle Hypotonia pathology, Muscle Weakness genetics, Muscle Weakness pathology, Mutation, Missense genetics, Myasthenic Syndromes, Congenital complications, Myasthenic Syndromes, Congenital pathology, Pedigree, Phenotype, Synaptic Transmission genetics, Genetic Predisposition to Disease, Muscle Hypotonia genetics, Myasthenic Syndromes, Congenital genetics, Synaptotagmin II genetics
Abstract

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications., (© 2020 Wiley Periodicals LLC.)

Published
2020
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3. De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Author

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, and Houlden H

Subjects
Alleles, Amino Acyl-tRNA Synthetases genetics, Cell Line, Female, Genetic Predisposition to Disease genetics, Humans, Male, Pedigree, RNA, Transfer genetics, Stem Cells physiology, Aspartate-tRNA Ligase genetics, Gain of Function Mutation genetics, Loss of Function Mutation genetics, Neurodevelopmental Disorders genetics, RNA, Transfer, Amino Acyl genetics
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., (Copyright © 2020. Published by Elsevier Inc.)

Published
2020
Full Text
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