Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5 .

Autor:	Rajan DS; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Kour S; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Fortuna TR; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States., Cousin MA; Department of Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States.; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States., Barnett SS; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States., Niu Z; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States., Babovic-Vuksanovic D; Department of Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States., Klee EW; Department of Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States.; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, United States.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States., Kirmse B; Division of Genetics, University of Mississippi Medical Center, Jackson, MS, United States., Innes M; Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Rydning SL; Department of Neurology, Oslo University Hospital, Oslo, Norway., Selmer KK; Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital and the University of Oslo, Oslo, Norway., Vigeland MD; Department of Medical Genetics, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway., Erichsen AK; Department of Ophthalmology, Oslo University Hospital, Oslo, Norway., Nemeth AH; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom., Millan F; GeneDx, Gaithersburg, MD, United States., DeVile C; Great Ormond Street Hospital, London, United Kingdom., Fawcett K; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.; Department of Health Sciences, University of Leicester, Leicester, United Kingdom., Legendre A; Laboratoire de biologie médicale multisites Seqoia-FMG2025, Paris, France., Sims D; Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom., Schnekenberg RP; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom., Burglen L; Centre 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.; Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France., Mercier S; CHU Nantes, Service de génétique médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Nantes, France.; Nantes Université, CNRS, INSERM, l’institut du thorax, Nantes, France., Bakhtiari S; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, United States.; Departments of Child Health, Neurology, Cellular and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine—Phoenix, Phoenix, AZ, United States., Francisco-Velilla R; Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain., Embarc-Buh A; Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain., Martinez-Salas E; Centro de Biologia Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain., Wigby K; Department of Pediatrics, University of California San Diego, San Diego, CA, United States.; Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States., Lenberg J; Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States., Friedman JR; Department of Neurosciences, University of California San Diego, San Diego, CA, United States.; Department of Pediatrics, University of California San Diego, San Diego, CA, United States.; Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States., Kruer MC; Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, United States.; Departments of Child Health, Neurology, Cellular and Molecular Medicine and Program in Genetics, University of Arizona College of Medicine—Phoenix, Phoenix, AZ, United States., Pandey UB; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2022 Feb 28; Vol. 10, pp. 783762. Date of Electronic Publication: 2022 Feb 28 (Print Publication: 2022).
DOI:	10.3389/fcell.2022.783762
Abstrakt:	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. Competing Interests: FM is employed by GeneDx (MD, USA). JF conducts Clinical Trials with Biogen (Angelman’s Syndrome). JF’s spouse is Founder and Principal of Friedman Bioventure, which holds a variety of publicly traded and private biotechnology interests. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Rajan, Kour, Fortuna, Cousin, Barnett, Niu, Babovic-Vuksanovic, Klee, Kirmse, Innes, Rydning, Selmer, Vigeland, Erichsen, Nemeth, Millan, DeVile, Fawcett, Legendre, Sims, Schnekenberg, Burglen, Mercier, Bakhtiari, Francisco-Velilla, Embarc-Buh, Martinez-Salas, Wigby, Lenberg, Friedman, Kruer and Pandey.)
Databáze:	MEDLINE
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