Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder
| العنوان: | Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder |
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| المؤلفون: | Danielle C. Lynch, Jia Wang, Aurora Pujol, Henry Houlden, Diana Castro, Xiaodong Wang, Jan Senderek, Shade B. Moody, Melissa Gibbons, Tim M. Strom, Abigail Collins, Jong Hee Chae, John Landers, Udai Bhan Pandey, Tyler R. Fortuna, Reza Maroofian, Hannah R. McCurry, Andrea H. Németh, Yuehua Zhang, Nathalie Boddaert, Carsten G. Bönnemann, Sabine Rudnik-Schöneborn, Vincent Cantagrel, Kali Juliette, Jeanne Amiel, Amber Begtrup, Sangmoon Lee, David Schorling, Chanika Phornphutkul, Konrad Platzer, E. Corina Andriescu, Roser Urreizti, Eric N. Anderson, Cyril Gitiaux, Randal Richardson, Maha S. Zaki, Matias Wagner, Hasnaa M. Elbendary, Dhivyaa Rajasundaram, Brian Kirmse, Murim Choi, Sandra Donkervoort, Joseph G. Gleeson, Steffen Leiz, Mahmoud Y. Issa, Valentina Stanley, Patrick Frosk, Siri Lynne Rydning, Karine Siquier, Janbernd Kirschner, Sameer Agnihotri, Sarah S. Barnett, Isabelle Desguerre, Michele Yang, Yong Beom Shin, Deepa S. Rajan, Margot A. Cousin, Andrés Nascimento Osorio, A. Micheil Innes, Ying Yang, Elliot S. Stolerman, Youngha Lee, Kimberly McDonald, Alberto Garcia-Oguiza, Edgard Verdura, Caroline Ward, Maria J. Guillen Sacoto, Minghui Wang, Sukhleen Kour, Kaja Kristine Selmer |
| المصدر: | NATURE COMMUNICATIONS r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Nature Communications r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Universidad de Alicante (UA) Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Developmental Disabilities, General Physics and Astronomy, 0302 clinical medicine, Neurodevelopmental disorder, Loss of Function Mutation, RNA-Seq, Neurons, Regulation of gene expression, Myoclonic Cerebellar Dyssynergia, Multidisciplinary, Neurodevelopmental disorders, Developmental disorders, Rigor Mortis, Gene Expression Regulation, Developmental, SMN Complex Proteins, Ribonucleoproteins, Small Nuclear, Hypotonia, Pedigree, Cell biology, medicine.anatomical_structure, Child, Preschool, Gene Knockdown Techniques, Muscle Hypotonia, Drosophila, Female, medicine.symptom, Ataxia, Science, Induced Pluripotent Stem Cells, Biology, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, snRNP, Amino Acid Sequence, Alleles, Loss function, Cerebellar ataxia, General Chemistry, Motor neuron, medicine.disease, Gene Ontology, HEK293 Cells, 030104 developmental biology, 030217 neurology & neurosurgery |
| الوصف: | 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. GEMIN5, an RNA-binding protein, is required for formation of small nuclear ribonucleoproteins. Here, the authors identify loss of function mutations in GEMIN5 that are associated with a human neurodevelopmental disorder. |
| وصف الملف: | application/pdf |
| تدمد: | 2041-1723 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1ed9687e3344ab597c47489b1520ba6f https://doi.org/10.1038/s41467-021-22627-w |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....1ed9687e3344ab597c47489b1520ba6f |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20411723 |
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