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

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.

STING Operation at the ER/Golgi Interface

“…GBF1 is involved in the formation of COP-I vesicles, maintenance, and function of the Golgi. The pathogenic variants of GBF-1 are recently found in individuals affected by distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) ( 61 ). It is tempting to speculate that STING is constitutively activated in these neurodegenerative diseases, as in the COPA syndrome, contributing in part to their pathogenesis.…”

The Regulatory Role of GBF1 on Osteoclast Activation Through EIF2a Mediated ER Stress and Novel Marker FAM129A Induction

“…Thus, in addition to directly acting on vesicular transport in the early secretory pathway, GBF1 also has a significant impact on maintaining the structural integrity and dynamic alteration of the Golgi apparatus ( Magliozzi et al, 2018 ). Furthermore, emerging evidence has revealed that GBF1 regulated different cycles of RNA replication in several virus families ( Martínez and Arias, 2020 ), participated in mitochondrial migration and localization ( Ackema et al, 2014 ), and affected the occurrence and development of neurodegenerative diseases ( Mendoza-Ferreira et al, 2020 ).…”

The Capillary Morphogenesis Gene 2 Triggers the Intracellular Hallmarks of Collagen VI-Related Muscular Dystrophy

“…In summary, heterozygous G-to-A substitution at position 877 in exon 10 of COL6A1 triggers the production of an altered extracellular collagen VI network that subsequently triggers the phosphorylation of the collagen VI receptor CMG2, an accumulation of endosomes and lysosomes and altered mitochondria and Golgi apparatus morphology in human fibroblasts. It has become clear that the ECM has profound effects on many cellular processes [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 ]. Consequently, this work exploits the opportunity to provide clinicians with novel diagnostic tools for monitoring and treating neuromuscular disorders.…”