Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder PMID: 33963192

GLP-1 and Obesity Research

2026-08-18

Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder

Nat Commun. 2021 May 7;12(1):2558. doi: 10.1038/s41467-021-22627-w.

Sukhleen Kour ^# ¹ , Deepa S Rajan ^# ¹ , Tyler R Fortuna ¹ , Eric N Anderson ¹ , Caroline Ward ¹ , Youngha Lee ² , Sangmoon Lee ² , Yong Beom Shin ³ , Jong-Hee Chae ⁴ , Murim Choi ² ⁴ , Karine Siquier ⁵ , Vincent Cantagrel ⁵ , Jeanne Amiel ⁶ , Elliot S Stolerman ⁷ , Sarah S Barnett ⁸ , Margot A Cousin ⁹ , Diana Castro ¹⁰ , Kimberly McDonald ¹¹ , Brian Kirmse ¹² , Andrea H Nemeth ¹³ ¹⁴ , Dhivyaa Rajasundaram ¹⁵ , A Micheil Innes ¹⁶ , Danielle Lynch ¹⁶ , Patrick Frosk ¹⁷ , Abigail Collins ¹⁸ , Melissa Gibbons ¹⁸ , Michele Yang ¹⁸ , Isabelle Desguerre ¹⁹ , Nathalie Boddaert ²⁰ , Cyril Gitiaux ²¹ , Siri Lynne Rydning ²² , Kaja K Selmer ²³ , Roser Urreizti ²⁴ , Alberto Garcia-Oguiza ²⁵ , Andrés Nascimento Osorio ²⁶ , Edgard Verdura ²⁷ , Aurora Pujol ²⁷ ²⁸ , Hannah R McCurry ²⁹ , John E Landers ³⁰ , Sameer Agnihotri ³¹ , E Corina Andriescu ³² , Shade B Moody ³² , Chanika Phornphutkul ³³ , Maria J Guillen Sacoto ³⁴ , Amber Begtrup ³⁴ , Henry Houlden ³⁵ , Janbernd Kirschner ³⁶ , David Schorling ³⁶ , Sabine Rudnik-Schöneborn ³⁷ , Tim M Strom ³⁸ , Steffen Leiz ³⁹ , Kali Juliette ⁴⁰ , Randal Richardson ⁴⁰ , Ying Yang ⁴¹ , Yuehua Zhang ⁴¹ , Minghui Wang ⁴² , Jia Wang ⁴³ , Xiaodong Wang ⁴³ , Konrad Platzer ⁴⁴ , Sandra Donkervoort ⁴⁵ , Carsten G Bönnemann ⁴⁵ , Matias Wagner ⁴⁶ , Mahmoud Y Issa ⁴⁷ , Hasnaa M Elbendary ⁴⁷ , Valentina Stanley ⁴⁸ , Reza Maroofian ³⁵ , Joseph G Gleeson ⁴⁸ , Maha S Zaki ⁴⁷ , Jan Senderek ⁴⁹ , Udai Bhan Pandey ⁵⁰ ⁵¹ ⁵²

Affiliations

1. Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
2. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
3. Department of Rehabilitative Medicine, Pusan National University School of Medicine, Pusan, Republic of Korea.
4. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
5. Developmental Brain Disorders Laboratory, Paris University, Imagine Institute, INSERM UMR, Paris, France.
6. Department of Genetics, AP-HP, Necker Enfants Malades Hospital, Paris University, Imagine Institute, Paris, France.
7. Greenwood Genetic Center, Greenwood, SC, USA.
8. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
9. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
10. Department of Pediatrics and Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
11. University of Mississippi Medical Center, Jackson, MS, USA.
12. Division of Genetics, University of Mississippi Medical Center, Jackson, MS, USA.
13. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
14. Oxford Centre for Genomic Medicine, Oxford University Hospitals National Health Service Foundation Trust, Oxford, UK.
15. Department of Pediatrics, Division of Health Informatics, Childrens Hospital of Pittsburgh, Pittsburgh, PA, USA.
16. Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
17. Department of Biochemistry and Medical Genetics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
18. Department of Pediatrics and Neurology, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, CO, USA.
19. Department of Pediatric Neurology, AP-HP, Necker Enfants Malades Hospital, Paris University Imagine Institute, Paris, France.
20. Department of Pediatric Radiology, AP-HP, Necker Enfants Malades Hospital, Paris University Imagine Institute, Paris, France.
21. Department of Pediatric Neurophysiology AP-HP, Necker Enfants Malades Hospital, Paris University, Paris, France.
22. Department of Neurology, Oslo University Hospital, Oslo, Norway.
23. Department of Research and Development, Division of Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway.
24. Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu and CIBERER, Barcelona, Spain.
25. Hospital Universitario Miguel Servet, Zaragoza, Spain.
26. Hospital Sant Joan de Déu, Barcelona, Spain.
27. Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
28. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
29. Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
30. Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
31. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
32. Department of Pediatrics, University of Texas Health Science Center, Houston, TX, USA.
33. Department of Pediatrics, Division of Human Genetics, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.
34. GeneDx, Gaithersburg, MD, USA.
35. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
36. Department of Neuropediatrics and Muscle Disorders, Medical Center,, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
37. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
38. Institute of Human Genetics, Faculty of Medicine, Technical University Munich, Munich, Germany.
39. Clinic for Children and Adolescents Dritter Orden, Divison of Neuropediatrics, Munchen, Germany.
40. Department of Neurology, Gillette Children's Specialty Healthcare, St Paul, MN, USA.
41. Department of Pediatrics, Peking University First Hospital, Beijing, China.
42. The First People's Hospital of Changde City, Hunan, China.
43. Cipher Gene Ltd, Beijing, China.
44. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
45. Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
46. Institute of Human Genetics, Klinikum rechts der IsarTechnical, University of Munich, Munich, Germany.
47. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
48. Departments of Neurosciences and Pediatrics, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.
49. Department of Neurology, Friedrich-Baur-Institute, University Hospital, LMU Munich, Munich, Germany.
50. Department of Pediatrics, Childrens Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected].
51. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
52. Children's Neuroscience Institute, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [email protected].
# Contributed equally.

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.