2. Academic Validation
  3. De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation

De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation

  • Am J Hum Genet. 2020 Oct 1;107(4):763-777. doi: 10.1016/j.ajhg.2020.08.018.
Natalia Mendoza-Ferreira 1,  Mert Karakaya 1,  Nur Cengiz 1,  Danique Beijer 2,  Karlla W Brigatti 3,  Claudia Gonzaga-Jauregui 4,  Nico Fuhrmann 1,  Irmgard Hölker 1,  Maximilian P Thelen 1,  Sebastian Zetzsche 1,  Roman Rombo 1,  Erik G Puffenberger 3,  Peter De Jonghe 5,  Tine Deconinck 2,  Stephan Zuchner 6,  Kevin A Strauss 4,  Vincent Carson 3,  Bertold Schrank 7,  Gilbert Wunderlich 8,  Jonathan Baets 5,  Brunhilde Wirth 9
Affiliations

Affiliations

  • 1 Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, and Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
  • 2 Translational Neurosciences, Faculty of Medicine, University of Antwerp, B-2610 Wilrijk, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, B-2610 Wilrijk, Belgium.
  • 3 Clinic for Special Children, Strasburg, PA 17579, USA.
  • 4 Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, NY 10591, USA.
  • 5 Translational Neurosciences, Faculty of Medicine, University of Antwerp, B-2610 Wilrijk, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, B-2610 Wilrijk, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerpen University Hospital, B-2650 Edegem, Belgium.
  • 6 Dr. John T. Macdonald Foundation Department of Human Genetics and Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, 33136 FL, USA.
  • 7 DKD Helios Klinik, Department of Neurology, 65191 Wiesbaden, Germany.
  • 8 Department of Neurology and Center for Rare Diseases, University Hospital Cologne, 50931 Cologne, Germany.
  • 9 Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, and Institute for Genetics, University of Cologne, 50931 Cologne, Germany. Electronic address: brunhilde.wirth@uk-koeln.de.
PMID: 32937143 DOI: 10.1016/j.ajhg.2020.08.018
Abstract

Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic Sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo. Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.

Keywords

Charcot-Marie-Tooth neuropathy; GBF1; Golgi fragmentation; de novo; dominant variants; exome; genome; motor neuropathy; neuromuscular disorder; next-generation sequencing.

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