Frontiers in Cell and Developmental Biology (Feb 2022)
Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5
- Deepa S. Rajan,
- Sukhleen Kour,
- Tyler R. Fortuna,
- Margot A. Cousin,
- Margot A. Cousin,
- Sarah S. Barnett,
- Zhiyv Niu,
- Zhiyv Niu,
- Dusica Babovic-Vuksanovic,
- Dusica Babovic-Vuksanovic,
- Dusica Babovic-Vuksanovic,
- Eric W. Klee,
- Eric W. Klee,
- Eric W. Klee,
- Eric W. Klee,
- Brian Kirmse,
- Micheil Innes,
- Siri Lynne Rydning,
- Kaja K. Selmer,
- Magnus Dehli Vigeland,
- Anne Kjersti Erichsen,
- Andrea H. Nemeth,
- Francisca Millan,
- Catherine DeVile,
- Katherine Fawcett,
- Katherine Fawcett,
- Adrien Legendre,
- David Sims,
- Ricardo Parolin Schnekenberg,
- Lydie Burglen,
- Lydie Burglen,
- Sandra Mercier,
- Sandra Mercier,
- Somayeh Bakhtiari,
- Somayeh Bakhtiari,
- Rosario Francisco-Velilla,
- Azman Embarc-Buh,
- Encarnacion Martinez-Salas,
- Kristen Wigby,
- Kristen Wigby,
- Jerica Lenberg,
- Jennifer R. Friedman,
- Jennifer R. Friedman,
- Jennifer R. Friedman,
- Michael C. Kruer,
- Michael C. Kruer,
- Udai Bhan Pandey
Affiliations
- Deepa S. Rajan
- Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Sukhleen Kour
- Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Tyler R. Fortuna
- Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Margot A. Cousin
- Department of Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
- Margot A. Cousin
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
- Sarah S. Barnett
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- Zhiyv Niu
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- Zhiyv Niu
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
- Dusica Babovic-Vuksanovic
- Department of Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
- Dusica Babovic-Vuksanovic
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- Dusica Babovic-Vuksanovic
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
- Eric W. Klee
- Department of Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
- Eric W. Klee
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States
- Eric W. Klee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- Eric W. Klee
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
- Brian Kirmse
- Division of Genetics, University of Mississippi Medical Center, Jackson, MS, United States
- Micheil Innes
- Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Siri Lynne Rydning
- Department of Neurology, Oslo University Hospital, Oslo, Norway
- Kaja K. Selmer
- Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway
- Magnus Dehli Vigeland
- 0Department of Medical Genetics, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Anne Kjersti Erichsen
- 1Department of Ophthalmology, Oslo University Hospital, Oslo, Norway
- Andrea H. Nemeth
- 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
- Francisca Millan
- 3GeneDx, Gaithersburg, MD, United States
- Catherine DeVile
- 4Great Ormond Street Hospital, London, United Kingdom
- Katherine Fawcett
- 5Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Katherine Fawcett
- 6Department of Health Sciences, University of Leicester, Leicester, United Kingdom
- Adrien Legendre
- 7Laboratoire de biologie médicale multisites Seqoia—FMG2025, Paris, France
- David Sims
- 5Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Ricardo Parolin Schnekenberg
- 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
- Lydie Burglen
- 8Centre de Référence des Malformations et Maladies Congénitales du Cervelet et Laboratoire de Neurogénétique Moléculaire, Département de Génétique, AP-HP. Sorbonne Université, Hôpital Trousseau, Paris, France
- Lydie Burglen
- 9Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France
- Sandra Mercier
- 6CHU Nantes, Service de génétique médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Nantes, France
- Sandra Mercier
- 7Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France
- Somayeh Bakhtiari
- 0Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
- Somayeh Bakhtiari
- 1Departments of Child Health, Neurology, Cellular and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine—Phoenix, Phoenix, AZ, United States
- Rosario Francisco-Velilla
- 2Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
- Azman Embarc-Buh
- 2Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
- Encarnacion Martinez-Salas
- 2Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain
- Kristen Wigby
- 4Department of Pediatrics, University of California San Diego, San Diego, CA, United States
- Kristen Wigby
- 5Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States
- Jerica Lenberg
- 5Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States
- Jennifer R. Friedman
- 3Department of Neurosciences, University of California San Diego, San Diego, CA, United States
- Jennifer R. Friedman
- 4Department of Pediatrics, University of California San Diego, San Diego, CA, United States
- Jennifer R. Friedman
- 5Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States
- Michael C. Kruer
- 0Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
- Michael C. Kruer
- 1Departments of Child Health, Neurology, Cellular and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine—Phoenix, Phoenix, AZ, United States
- Udai Bhan Pandey
- Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- DOI
- https://doi.org/10.3389/fcell.2022.783762
- Journal volume & issue
-
Vol. 10
Abstract
The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.
Keywords
