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Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Kour, Sukhleen ; Rajan, Deepa S ; Fortuna, Tyler R ; Anderson, Eric N ; Ward, Caroline ; Lee, Youngha ; Lee, Sangmoon ; Shin, Yong Beom ; Chae, Jong-Hee ; Choi, Murim ; Siquier, Karine ; Cantagrel, Vincent ; Amiel, Jeanne ; Stolerman, Elliot S ; Barnett, Sarah S ; Cousin, Margot A ; Castro, Diana ; McDonald, Kimberly ; Kirmse, Brian ; Nemeth, Andrea H ; Rajasundaram, Dhivyaa ; Innes, A Micheil ; Lynch, Danielle ; Frosk, Patrick ; Collins, Abigail ; Gibbons, Melissa ; Yang, Michele ; Desguerre, Isabelle ; Boddaert, Nathalie ; Gitiaux, Cyril ; Rydning, Siri Lynne ; Selmer, Kaja K ; Urreizti, Roser ; Garcia-Oguiza, Alberto ; Osorio, Andrés Nascimento ; Verdura, Edgard ; Pujol, Aurora ; McCurry, Hannah R ; Landers, John E ; Agnihotri, Sameer ; Andriescu, E Corina ; Moody, Shade B ; Phornphutkul, Chanika ; Sacoto, Maria J Guillen ; Begtrup, Amber ; Houlden, Henry ; Kirschner, Janbernd ; Schorling, David ; Rudnik-Schöneborn, Sabine ; Strom, Tim M ; Leiz, Steffen ; Juliette, Kali ; Richardson, Randal ; Yang, Ying ; Zhang, Yuehua ; Wang, Minghui ; Wang, Jia ; Wang, Xiaodong ; Platzer, Konrad ; Donkervoort, Sandra ; Bönnemann, Carsten G ; Wagner, Matias ; Issa, Mahmoud Y ; Elbendary, Hasnaa M ; Stanley, Valentina ; Maroofian, Reza ; Gleeson, Joseph G ; Zaki, Maha S ; Senderek, Jan ; Pandey, Udai Bhan

Nature communications, 2021-05, Vol.12 (1), p.2558-2558, Article 2558 [Revista revisada por pares]

England: Nature Publishing Group

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Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder
Autor: Kour, Sukhleen ; Rajan, Deepa S ; Fortuna, Tyler R ; Anderson, Eric N ; Ward, Caroline ; Lee, Youngha ; Lee, Sangmoon ; Shin, Yong Beom ; Chae, Jong-Hee ; Choi, Murim ; Siquier, Karine ; Cantagrel, Vincent ; Amiel, Jeanne ; Stolerman, Elliot S ; Barnett, Sarah S ; Cousin, Margot A ; Castro, Diana ; McDonald, Kimberly ; Kirmse, Brian ; Nemeth, Andrea H ; Rajasundaram, Dhivyaa ; Innes, A Micheil ; Lynch, Danielle ; Frosk, Patrick ; Collins, Abigail ; Gibbons, Melissa ; Yang, Michele ; Desguerre, Isabelle ; Boddaert, Nathalie ; Gitiaux, Cyril ; Rydning, Siri Lynne ; Selmer, Kaja K ; Urreizti, Roser ; Garcia-Oguiza, Alberto ; Osorio, Andrés Nascimento ; Verdura, Edgard ; Pujol, Aurora ; McCurry, Hannah R ; Landers, John E ; Agnihotri, Sameer ; Andriescu, E Corina ; Moody, Shade B ; Phornphutkul, Chanika ; Sacoto, Maria J Guillen ; Begtrup, Amber ; Houlden, Henry ; Kirschner, Janbernd ; Schorling, David ; Rudnik-Schöneborn, Sabine ; Strom, Tim M ; Leiz, Steffen ; Juliette, Kali ; Richardson, Randal ; Yang, Ying ; Zhang, Yuehua ; Wang, Minghui ; Wang, Jia ; Wang, Xiaodong ; Platzer, Konrad ; Donkervoort, Sandra ; Bönnemann, Carsten G ; Wagner, Matias ; Issa, Mahmoud Y ; Elbendary, Hasnaa M ; Stanley, Valentina ; Maroofian, Reza ; Gleeson, Joseph G ; Zaki, Maha S ; Senderek, Jan ; Pandey, Udai Bhan
Materias: Alleles ; Amino Acid Sequence ; Animals ; Assembly ; Ataxia ; Cerebellar ataxia ; Cerebellum ; Child, Preschool ; Developmental Disabilities - genetics ; Drosophila - genetics ; Drosophila - growth & development ; Female ; Gene Expression Regulation, Developmental - genetics ; Gene Knockdown Techniques ; Gene Ontology ; HEK293 Cells ; Homology ; Humans ; Hypotonia ; Induced Pluripotent Stem Cells - metabolism ; Life span ; Loss of Function Mutation ; Male ; Muscle Hypotonia - genetics ; Mutation ; Myoclonic Cerebellar Dyssynergia - genetics ; Neurodevelopmental disorders ; Neurodevelopmental Disorders - diagnostic imaging ; Neurodevelopmental Disorders - genetics ; Neurodevelopmental Disorders - metabolism ; Neurodevelopmental Disorders - physiopathology ; Neurons ; Neurons - metabolism ; Pedigree ; Polymorphism, Single Nucleotide ; Proteins ; Ribonucleic acid ; Ribonucleoproteins ; Ribonucleoproteins (small nuclear) ; Ribonucleoproteins, Small Nuclear - genetics ; Ribonucleoproteins, Small Nuclear - metabolism ; Rigor Mortis - genetics ; RNA ; RNA-binding protein ; RNA-Seq ; SMN Complex Proteins - genetics ; SMN Complex Proteins - metabolism ; Spliceosomes
Es parte de: Nature communications, 2021-05, Vol.12 (1), p.2558-2558, Article 2558
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Descripción: 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.
Editor: England: Nature Publishing Group
Idioma: Inglés;Noruego

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Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

England: Nature Publishing Group

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