Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Sukhleen Kour, Deepa S. Rajan, Tyler R. Fortuna, Eric N. Anderson, Caroline Ward, Youngha Lee, Sangmoon Lee, Yong Beom Shin, Jong-Hee Chae, Murim Choi, Karine Siquier, Vincent Cantagrel, Jeanne Amiel, Elliot S. Stolerman, Sarah S. Barnett, Margot A. Cousin, Diana Castro, Kimberly McDonald, Brian Kirmse, Andrea H. Nemeth, Dhivyaa Rajasundaram, A. Micheil Innes, Danielle Lynch, Patrick Frosk, Abigail Collins, Melissa Gibbons, Michele Yang, Isabelle Desguerre, Nathalie Boddaert, Cyril Gitiaux, Siri Lynne Rydning, Kaja K. Selmer, Roser Urreizti, Alberto Garcia-Oguiza, Andrés Nascimento Osorio, Edgard Verdura, Aurora Pujol, Hannah R. McCurry, John E. Landers, Sameer Agnihotri, E. Corina Andriescu, Shade B. Moody, Chanika Phornphutkul, Maria J. Guillen Sacoto, Amber Begtrup, Henry Houlden, Janbernd Kirschner, David Schorling, Sabine Rudnik-Schöneborn, Tim M. Strom, Steffen Leiz, Kali Juliette, Randal Richardson, Ying Yang, Yuehua Zhang, Minghui Wang, Jia Wang, Xiaodong Wang, Konrad Platzer, Sandra Donkervoort, Carsten G. Bönnemann, Matias Wagner, Mahmoud Y. Issa, Hasnaa M. Elbendary, Valentina Stanley, Reza Maroofian, Joseph G. Gleeson, Maha S. Zaki, Jan Senderek and Udai Bhan Pandey ()
Additional contact information
Sukhleen Kour: University of Pittsburgh Medical Center
Deepa S. Rajan: University of Pittsburgh Medical Center
Tyler R. Fortuna: University of Pittsburgh Medical Center
Eric N. Anderson: University of Pittsburgh Medical Center
Caroline Ward: University of Pittsburgh Medical Center
Youngha Lee: Seoul National University College of Medicine
Sangmoon Lee: Seoul National University College of Medicine
Yong Beom Shin: Pusan National University School of Medicine
Jong-Hee Chae: Seoul National University College of Medicine
Murim Choi: Seoul National University College of Medicine
Karine Siquier: INSERM UMR
Vincent Cantagrel: INSERM UMR
Jeanne Amiel: Imagine Institute
Elliot S. Stolerman: Greenwood Genetic Center
Sarah S. Barnett: Mayo Clinic
Margot A. Cousin: Mayo Clinic
Diana Castro: University of Texas Southwestern Medical Center
Kimberly McDonald: University of Mississippi Medical Center
Brian Kirmse: University of Mississippi Medical Center
Andrea H. Nemeth: University of Oxford
Dhivyaa Rajasundaram: Childrens Hospital of Pittsburgh
A. Micheil Innes: University of Calgary
Danielle Lynch: University of Calgary
Patrick Frosk: University of Manitoba
Abigail Collins: University of Colorado School of Medicine
Melissa Gibbons: University of Colorado School of Medicine
Michele Yang: University of Colorado School of Medicine
Isabelle Desguerre: Paris University Imagine Institute
Nathalie Boddaert: Paris University Imagine Institute
Cyril Gitiaux: Paris University
Siri Lynne Rydning: Oslo University Hospital
Kaja K. Selmer: Oslo University Hospital and the University of Oslo
Roser Urreizti: Institut de Recerca Sant Joan de Déu and CIBERER
Alberto Garcia-Oguiza: Hospital Universitario Miguel Servet
Andrés Nascimento Osorio: Hospital Sant Joan de Déu
Edgard Verdura: Instituto de Salud Carlos III
Aurora Pujol: Instituto de Salud Carlos III
Hannah R. McCurry: Broad Institute of MIT and Harvard
John E. Landers: University of Massachusetts Medical School
Sameer Agnihotri: University of Pittsburgh School of Medicine
E. Corina Andriescu: University of Texas Health Science Center
Shade B. Moody: University of Texas Health Science Center
Chanika Phornphutkul: Rhode Island Hospital and Warren Alpert Medical School of Brown University
Maria J. Guillen Sacoto: GeneDx
Amber Begtrup: GeneDx
Henry Houlden: UCL Queen Square Institute of Neurology
Janbernd Kirschner: Faculty of Medicine, University of Freiburg
David Schorling: Faculty of Medicine, University of Freiburg
Sabine Rudnik-Schöneborn: Medical University Innsbruck
Tim M. Strom: Technical University Munich
Steffen Leiz: Divison of Neuropediatrics
Kali Juliette: Gillette Children’s Specialty Healthcare
Randal Richardson: Gillette Children’s Specialty Healthcare
Ying Yang: Peking University First Hospital
Yuehua Zhang: Peking University First Hospital
Minghui Wang: The First People’s Hospital of Changde City
Jia Wang: Cipher Gene Ltd
Xiaodong Wang: Cipher Gene Ltd
Konrad Platzer: University of Leipzig Medical Center
Sandra Donkervoort: National Institutes of Health
Carsten G. Bönnemann: National Institutes of Health
Matias Wagner: University of Munich
Mahmoud Y. Issa: Human Genetics and Genome Research Division, National Research Centre
Hasnaa M. Elbendary: Human Genetics and Genome Research Division, National Research Centre
Valentina Stanley: University of California, San Diego
Reza Maroofian: UCL Queen Square Institute of Neurology
Joseph G. Gleeson: University of California, San Diego
Maha S. Zaki: Human Genetics and Genome Research Division, National Research Centre
Jan Senderek: LMU Munich
Udai Bhan Pandey: University of Pittsburgh Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22627-w

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