Mendoza-Ferreira, Natalia, Karakaya, Mert, Cengiz, Nur, Beijer, Danique ORCID: 0000-0001-6593-7644, Brigatti, Karlla W., Gonzaga-Jauregui, Claudia, Fuhrmann, Nico, Hoelker, Irmgard, Thelen, Maximilian P., Zetzsche, Sebastian, Rombo, Roman, Puffenberger, Erik G., De Jonghe, Peter, Deconinck, Tine, Zuchner, Stephan, Strauss, Kevin A., Carson, Vincent, Schrank, Bertold, Wunderlich, Gilbert, Baets, Jonathan and Wirth, Brunhilde (2020). De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation. Am. J. Hum. Genet., 107 (4). S. 763 - 778. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mendoza-Ferreira, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karakaya, MertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cengiz, NurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beijer, DaniqueUNSPECIFIEDorcid.org/0000-0001-6593-7644UNSPECIFIED
Brigatti, Karlla W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzaga-Jauregui, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuhrmann, NicoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelker, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, Maximilian P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zetzsche, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rombo, RomanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puffenberger, Erik G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deconinck, TineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuchner, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strauss, Kevin A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carson, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrank, BertoldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, GilbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baets, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-316810
DOI: 10.1016/j.ajhg.2020.08.018
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 107
Number: 4
Page Range: S. 763 - 778
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NUCLEOTIDE EXCHANGE FACTOR; SPINAL MUSCULAR-ATROPHY; MARIE-TOOTH-DISEASE; HEREDITARY MOTOR; SEC7 DOMAIN; CIS-GOLGI; ARF-GEF; MUTATION; TRANSPORT; FAMILYMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31681

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item