Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Autor: 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
Rok vydání: 2021
Předmět:
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
Zdroj: 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)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-22627-w
Popis: 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.
Databáze: OpenAIRE
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