TY - JOUR
T1 - De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation
AU - Mendoza-Ferreira, Natalia
AU - Karakaya, Mert
AU - Cengiz, Nur
AU - Beijer, Danique
AU - Brigatti, Karlla W.
AU - Gonzaga-Jauregui, Claudia
AU - Fuhrmann, Nico
AU - Hölker, Irmgard
AU - Thelen, Maximilian P.
AU - Zetzsche, Sebastian
AU - Rombo, Roman
AU - Puffenberger, Erik G.
AU - De Jonghe, Peter
AU - Deconinck, Tine
AU - Zuchner, Stephan
AU - Strauss, Kevin A.
AU - Carson, Vincent
AU - Schrank, Bertold
AU - Wunderlich, Gilbert
AU - Baets, Jonathan
AU - Wirth, Brunhilde
N1 - Funding Information:
We would like to thank the family members described herein for participating in this study. We thank all our clinical collaborators for the support at clinical follow-up, diagnostics, and the genetic analysis. We furthermore thank the Regional Computing Center of the University of Cologne (RZZK) for providing computing time and storage on the CHEOPS high performance computing cluster. This work was supported by the Deutsche Forschungsgemeinschaft (Wi945/19-1 and RTG 1960 to B.W.), NRW Innovation Award (B.W.), the European Community's Seventh Framework Programme (FP7/2007?2013) under grant 2012-305121 (NEUROMICS) (B.W. and J.B.), the Center for Molecular Medicine Cologne (C18 to B.W. and M.K.), the Association Belge contre les Maladies Neuromusculaire (ABMM)?Aide ? la Recherche ASBL (2017-2018/05) (D.B. and J.B.). J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund-Flanders (FWO) under grant 1805016N. We are thankful for access to the GENESIS analysis platform and Varbank analysis platform.
Funding Information:
We would like to thank the family members described herein for participating in this study. We thank all our clinical collaborators for the support at clinical follow-up, diagnostics, and the genetic analysis. We furthermore thank the Regional Computing Center of the University of Cologne (RZZK) for providing computing time and storage on the CHEOPS high performance computing cluster. This work was supported by the Deutsche Forschungsgemeinschaft ( Wi945/19-1 and RTG 1960 to B.W.), NRW Innovation Award (B.W.), the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant 2012-305121 (NEUROMICS) (B.W. and J.B.), the Center for Molecular Medicine Cologne ( C18 to B.W. and M.K.), the Association Belge contre les Maladies Neuromusculaire (ABMM)—Aide à la Recherche ASBL ( 2017-2018/05 ) (D.B. and J.B.). J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund-Flanders (FWO) under grant 1805016N . We are thankful for access to the GENESIS analysis platform and Varbank analysis platform.
Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
KW - Charcot-Marie-Tooth neuropathy
KW - GBF1
KW - Golgi fragmentation
KW - de novo
KW - dominant variants
KW - exome
KW - genome
KW - motor neuropathy
KW - neuromuscular disorder
KW - next-generation sequencing
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UR - http://www.scopus.com/inward/citedby.url?scp=85091632251&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2020.08.018
DO - 10.1016/j.ajhg.2020.08.018
M3 - Article
C2 - 32937143
AN - SCOPUS:85091632251
VL - 107
SP - 763
EP - 777
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -