Kour, S;
Rajan, DS;
Fortuna, TR;
Anderson, EN;
Ward, C;
Lee, Y;
Lee, S;
Shin, YB;
Chae, J-H;
Choi, M;
et al.
Kour, S; Rajan, DS; Fortuna, TR; Anderson, EN; Ward, C; Lee, Y; Lee, S; Shin, YB; Chae, J-H; Choi, M; Siquier, K; Cantagrel, V; Amiel, J; Stolerman, ES; Barnett, SS; Cousin, MA; Castro, D; McDonald, K; Kirmse, B; Nemeth, AH; Rajasundaram, D; Innes, AM; Lynch, D; Frosk, P; Collins, A; Gibbons, M; Yang, M; Desguerre, I; Boddaert, N; Gitiaux, C; Rydning, SL; Selmer, KK; Urreizti, R; Garcia-Oguiza, A; Osorio, AN; Verdura, E; Pujol, A; McCurry, HR; Landers, JE; Agnihotri, S; Andriescu, EC; Moody, SB; Phornphutkul, C; Sacoto, MJG; Begtrup, A; Houlden, H; Kirschner, J; Schorling, D; Rudnik-Schöneborn, S; Strom, TM; Leiz, S; Juliette, K; Richardson, R; Yang, Y; Zhang, Y; Wang, M; Wang, J; Wang, X; Platzer, K; Donkervoort, S; Bönnemann, CG; Wagner, M; Issa, MY; Elbendary, HM; Stanley, V; Maroofian, R; Gleeson, JG; Zaki, MS; Senderek, J; Pandey, UB
(2021)
Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.
Nat Commun, 12 (1).
p. 2558.
ISSN 2041-1723
https://doi.org/10.1038/s41467-021-22627-w
SGUL Authors: Maroofian, Reza
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Abstract
GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.
Item Type: | Article | |||||||||||||||||||||||||||
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Additional Information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2021 | |||||||||||||||||||||||||||
Keywords: | Alleles, Amino Acid Sequence, Animals, Child, Preschool, Developmental Disabilities, Drosophila, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Ontology, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Muscle Hypotonia, Myoclonic Cerebellar Dyssynergia, Neurodevelopmental Disorders, Neurons, Pedigree, Polymorphism, Single Nucleotide, RNA-Seq, Ribonucleoproteins, Small Nuclear, Rigor Mortis, SMN Complex Proteins, Neurons, Animals, Humans, Drosophila, Myoclonic Cerebellar Dyssynergia, Muscle Hypotonia, Rigor Mortis, Ribonucleoproteins, Small Nuclear, Pedigree, Developmental Disabilities, Gene Expression Regulation, Developmental, Amino Acid Sequence, Polymorphism, Single Nucleotide, Alleles, Child, Preschool, Female, Male, SMN Complex Proteins, Gene Knockdown Techniques, Induced Pluripotent Stem Cells, HEK293 Cells, Gene Ontology, Neurodevelopmental Disorders, Loss of Function Mutation, RNA-Seq, MD Multidisciplinary | |||||||||||||||||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) | |||||||||||||||||||||||||||
Journal or Publication Title: | Nat Commun | |||||||||||||||||||||||||||
ISSN: | 2041-1723 | |||||||||||||||||||||||||||
Language: | eng | |||||||||||||||||||||||||||
Dates: |
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Publisher License: | Creative Commons: Attribution 4.0 | |||||||||||||||||||||||||||
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PubMed ID: | 33963192 | |||||||||||||||||||||||||||
Web of Science ID: | WOS:000656447400003 | |||||||||||||||||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/113391 | |||||||||||||||||||||||||||
Publisher's version: | https://doi.org/10.1038/s41467-021-22627-w |
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