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GOLGI-SPECIFIC BREFELDIN-A RESISTANCE FACTOR 1; GBF1

GOLGI-SPECIFIC BREFELDIN-A RESISTANCE FACTOR 1; GBF1

Alternative titles; symbolsKIAA0248HGNC Approved Gene Symbol: GBF1Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38): 10:102,230,642-102,382,898 (fr...

Alternative titles; symbols

  • KIAA0248

HGNC Approved Gene Symbol: GBF1

Cytogenetic location: 10q24.32 Genomic coordinates (GRCh38): 10:102,230,642-102,382,898 (from NCBI)

▼ Description
The GBF1 gene encodes a guanine-nucleotide exchange factor (GEF) of the Sec7 domain family that facilitates the GDP-to-GTP exchange for members of the ARF family of smaller GTPases. The activation of ARF proteins is crucial for the spatiotemporal regulation of membrane dynamics and cell organization. GBF1 plays a role in maintenance of the Golgi apparatus and also regulates mitochondrial dynamics (summary by Mendoza-Ferreira et al., 2020).

▼ Cloning and Expression
Members of the Sec7 domain family share a conserved region that forms a catalytic fold with guanine nucleotide exchange activity. In vitro, the Sec7 domain of several proteins catalyzes the activation of ADP-ribosylation factors (ARFs; see 103180), suggesting that members of the Sec7 domain family represent specific guanine nucleotide exchange factors for the ARF GTPase family. Nagase et al. (1996) isolated KIAA0248, a partial cDNA from immature myeloid cells encoding a protein with homology to S. cerevisiae Sec7. Using 5-prime RACE, Mansour et al. (1998) isolated a cDNA corresponding to the remainder of the coding sequence. They designated the gene GBF1 (Golgi-specific brefeldin A resistance factor-1). The predicted 1,859-amino acid protein has a pI of 5.55 and contains a Sec7 domain and a proline-rich C terminus. A 7-kb GBF1 mRNA was expressed in all tissues tested by Northern blot analysis.

Mendoza-Ferreira et al. (2020) found expression of the Gbf1 gene in murine motor neurons. There was abundant expression in neuronal soma, the Golgi apparatus, and the growth cone tip, where it localized to vesicle-like structures. There was a decrease in expression during neuronal differentiation in vitro. However, Gbf1 was present in protein lysates from the brain, spinal cord, and muscle of wildtype mice.

▼ Mapping
By analysis of a somatic cell hybrid panel and by fluorescence in situ hybridization, Mansour et al. (1998) mapped the GBF1 gene to 10q24. Another Sec7 domain family member, PSD (602327), maps to the same region.

▼ Molecular Genetics
In 7 patients from 4 unrelated families with dominant axonal Charcot-Marie-Tooth disease-2GG (CMT2GG; 606483), Mendoza-Ferreira et al. (2020) identified 4 different heterozygous mutations in the GBF1 gene (603698.0001-603698.0004). The mutations, which were found by whole-exome or whole-genome sequencing, were either absent or present at a very low frequency in the gnomAD database. There were 3 missense variants and 1 nonsense variant. The mutations occurred de novo in 2 individuals, was inherited from an unaffected mother in another, and segregated with the disorder in one of the families (family 2). Studies of patient fibroblasts showed fragmentation of the Golgi apparatus. Mendoza-Ferreira et al. (2020) hypothesized that pathogenic GBF1 mutations may compromise function of the Golgi apparatus and impair intracellular vesicular trafficking or anterograde/retrograde cargo movement.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2GG
GBF1, ALA1137VAL
In a 68-year-old man (patient 1) with axonal Charcot-Marie-Tooth disease type 2GG (CMT2GG; 606483), Mendoza-Ferreira et al. (2020) identified a de novo heterozygous c.3410C-T transition (c.3410C-T, NM_004193.3) in exon 28 of the GBF1 gene, resulting in an ala1137-to-val (A1137V) substitution at a conserved residue in the HDS2 domain. The mutation, which was found by trio-based whole-genome sequencing, was present in the heterozygous state in 2 individuals of African ancestry in the gnomAD database (frequency of 7 x 10(-06)), but the authors stated that this finding did not preclude it being a pathogenic variant since the disorder is age-dependent. Functional studies of the variant were not performed, but patient-derived fibroblasts showed fragmentation of the Golgi apparatus.

.0002 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2GG
GBF1, ARG1461GLN
In 4 members of a 3-generation Belgian family (family 2) with axonal Charcot-Marie-Tooth disease type 2GG (CMT2GG; 606483), Mendoza-Ferreira et al. (2020) identified a heterozygous c.4382G-A transition (c.4382G-A, NM_004193.3) in exon 33 of the GBF1 gene, resulting in an arg1461-to-gln (R1461Q) substitution at a conserved residue between the HDS2 and HDS3 domains. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant were not performed, but patient-derived fibroblasts showed fragmentation of the Golgi apparatus.

.0003 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2GG
GBF1, TRP1175TER
In 40-year-old Amish man with axonal Charcot-Marie-Tooth disease type 2GG (CMT2GG; 606483), Mendoza-Ferreira et al. (2020) identified a de novo heterozygous c.3525G-A transition (c.3525G-A, NM_004193.3) in exon 29 of the GBF1 gene, resulting in a trp1175-to-ter (W1175X) substitution in the HDS2 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed, but patient-derived fibroblasts showed fragmentation of the Golgi apparatus.

.0004 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2GG
GBF1, CYS982TYR
In a 54-year-old man (family 4) with axonal Charcot-Marie-Tooth disease type 2GG (CMT2GG; 606483), Mendoza-Ferreira et al. (2020) identified a heterozygous c.2945G-A transition (c.2945G-A, NM_004193.3) in exon 23 of the GBF1 gene, resulting in a cys982-to-tyr (C982Y) substitution at a conserved residue in the HDS1 domain. The mutation, which was inherited from his clinically unaffected 73-year-old mother, was not present in the gnomAD database. Although his mother had no neuromuscular complaints, electrophysiologic tests were not performed, so a subclinical phenotype could not be excluded. The findings could suggest incomplete penetrance. Functional studies of the variant were not performed, but patient-derived fibroblasts showed fragmentation of the Golgi apparatus.

Tags: 10q24.32