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GDP DISSOCIATION INHIBITOR 1; GDI1

GDP DISSOCIATION INHIBITOR 1; GDI1

Alternative titles; symbolsRAB GDP-DISSOCIATION INHIBITOR, ALPHA; RABGDIARAB GDI-ALPHARHOGDIOLIGOPHRENIN 2; OPHN2HGNC Approved Gene Symbol: GDI1Cytogenetic locat...

Alternative titles; symbols

  • RAB GDP-DISSOCIATION INHIBITOR, ALPHA; RABGDIA
  • RAB GDI-ALPHA
  • RHOGDI
  • OLIGOPHRENIN 2; OPHN2

HGNC Approved Gene Symbol: GDI1

Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:154,437,153-154,443,466 (from NCBI)

▼ Description
The GDP dissociation inhibitor-1 gene (GDI1) regulates the GDP-GTP exchange reaction of members of the rab family, small GTP-binding proteins of the ras superfamily, that are involved in vesicular trafficking of molecules between cellular organelles. The rab proteins undergo activation upon GTP binding, and GTP hydrolysis to GDP inactivates the protein. GDI proteins slow the rate of dissociation of GDP from rab proteins and release GDP from membrane-bound rabs (Bachner et al., 1995).

Chelly (1999) referred to the protein as oligophrenin-2 (OPHN2).

▼ Cloning and Expression
Matsui et al. (1990) cloned a bovine GDI gene, designated smg p25A, using an oligomer probe based on partial amino acid sequence. The 447-amino acid protein was expressed in E. coli and shown to have GDI activity. Sedlacek et al. (1994) noted 2 rat rab GDI sequences, designated alpha and beta, in the EMBL database (accession nos. X74401 and X74402).

Sedlacek et al. (1993) characterized a human rab GDI1 locus, which they called XAP-4. The predicted amino acid sequence of the protein is 98.4% identical to the bovine and rat GDI-alphas and 86.5% identical to human rab GDI-beta (GDI2; 600767). The rab GDI-alpha gene was expressed at highest levels as a 2.5-kb mRNA in brain, with lesser amounts in the muscle and kidney. Subsequent work by Bachner et al. (1995) showed expression predominantly in neural and sensory tissues.

D'Adamo et al. (1997) noted that GDI is expressed in all parts of the adult brain and, by in situ hybridization analysis, it is detectable in post-mitotic neural cells during mouse development, with the same timing and in the same cell types as Rab3a.

Shisheva et al. (1994) cloned and characterized the mouse gene.

▼ Gene Function
Rab GTPases regulate vesicle trafficking in eukaryotic cells by reversibly associating with lipid membranes. Inactive Rab GTPases are maintained in the cytosol by binding to GDP-dissociation inhibitor. It is believed that specialized proteins are required to displace GDI from Rab GTPases before Rab activation by GDP-GTP exchange factors (GEFs). Machner and Isberg (2007) found that SidM from Legionella pneumophila could act as both GEF and GDI-displacement factor (GDF) for Rab1 (179508). Rab1 released from GDI was inserted into liposomal membranes and was used as a substrate for SidM-mediated nucleotide exchange. During host cell infection, recruitment of Rab1 to Legionella-containing vacuoles depended on the GDF activity of SidM. Thus, Machner and Isberg (2007) concluded that GDF and GEF activity can be promoted by a single protein, and GDF activity can coordinate Rab1 recruitment from the GDI-bound pool.

▼ Gene Structure
Sedlacek et al. (1994) characterized the human RABGDIA gene, which has 11 exons in a span of about 7 kb.

▼ Biochemical Features
Hoffman et al. (2000) determined the 2.6-angstrom x-ray crystallographic structure of the GTP-binding protein CDC42 (116952) in complex with GDI1. The structure revealed 2 important sites of interaction between GDI1 and CDC42. First, the N-terminal regulatory arm of GDI1 binds to the switch I and II domains of CDC42, leading to inhibition of both GDP dissociation and GTP hydrolysis. Second, the geranylgeranyl moiety of CDC42 inserts into a hydrophobic pocket within the immunoglobulin-like domain of the GDI1 molecule, leading to membrane release. The structural data demonstrated how GDIs serve as negative regulators of small GTP-binding proteins and how the isoprenoid moiety is utilized in this critical regulatory interaction.

Rak et al. (2003) used a combination of chemical synthesis and protein engineering to generate and crystallize the monoprenylated YPT1-RABGDI complex. The structure of this complex was determined to 1.5-angstrom resolution and provided a structural basis for the ability of RABGDI to inhibit nucleotide release by RAB proteins. Isoprenoid binding requires a conformational change that opens a cavity in the hydrophobic core of its domain II. Analysis of the structure provided a molecular basis for understanding a RABGDI mutant that causes mental retardation.

▼ Mapping
Sedlacek et al. (1993) localized a human rab GDI locus, which they called XAP-4, near G6PD (305900) on chromosome Xq28. Sedlacek et al. (1994) found that RABGDIA is present in a gene-dense region of Xq28 with at least 8 other loci in the interval (approximately 220 kb) between QM (RPL10; 312173) and G6PD.

▼ Molecular Genetics
D'Adamo et al. (1997, 1998) demonstrated unique mutations in the RABGDIA gene in affected members of the MRX41 family (300104.0001) reported by Hamel et al. (1996) and the MRX48 family (300104.0002) reported by des Portes et al. (1997).

Bienvenu et al. (1998) carried out mutation screening of the whole coding region of the GDI1 gene, using a combination of denaturing gradient gel electrophoresis and direct sequencing, in 164 patients found negative for expansions across the FRAXA GCC repeat (309550.0004). The authors identified a novel missense mutation in exon 11 of the GDI1 gene (300104.0003) in a family with nonspecific mental retardation. In this large French family, all affected males showed moderate to severe mental retardation. X-linked semidominant inheritance was strongly suggested by the severe phenotypes in males in comparison to mildly affected females or unaffected obligate carriers. The study suggested that the prevalence of GDI1 mutations in nonspecific mental retardation may be 0.5 to 1%.

Vandewalle et al. (2009) demonstrated a novel X-linked mental retardation syndrome due to recurrent copy number gain of Xq28 specifically involving the GDI1 gene. Tiling Xq28 region-specific oligo array revealed that all aberrations started at the beginning of the low copy repeat LCR-K1 at position 153.20 Mb and ended just distal to LCR-L2 at 153.54 Mb. The copy number gain always included 18 annotated genes, of which RPL10 (312173), ATP6AP1 (300197), and GDI1 are highly expressed in brain. Of these, Vandewalle et al. (2009) considered GDI1 the most likely candidate. Its copy number correlated with the severity of clinical features: it was duplicated in a family with nonsyndromic moderate mental retardation, triplicated in males from 2 families with mild mental retardation and additional features, and present in 5 copies in a family with a severe syndromic form of mental retardation. Expression analysis showed copy number-dependent increased mRNA levels in affected patients compared to control individuals. Interestingly, analysis of the breakpoint regions suggested a recombination mechanism that involves 2 adjacent but different sets of low copy repeats.

▼ Evolution
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including GDI1, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.

▼ Animal Model
D'Adamo et al. (2002) reported the cognitive and behavioral characteristics of mice carrying a deletion of Gdi1. The Gdi1-deficient mice were fertile and anatomically normal, and exhibited normal spatial and episodic memory and emotional behavior. However, they were impaired in tasks requiring formation of short-term temporal associations, suggesting a defect in short-term memory. In addition, they showed lowered aggression and altered social behavior. In mice, as in humans, lack of Gdi1 spared most central nervous system functions and preferentially impaired only a few forebrain functions required to form temporal associations.

Using electron microscopy and electrophysiology, Bianchi et al. (2009) reported that lack of Gdi1 in mice impaired several steps in synaptic vesicle (SV) biogenesis and recycling in the hippocampus. Alteration of the SV reserve pool and a 50% reduction in the total number of SVs in adult synapses may be dependent on a defective endosomal-dependent recycling and may lead to the observed alterations in short-term plasticity. The short-term memory deficit in mutant mice, observed when using fear-conditioning protocols with short intervals between trials, disappeared when Gdi1-mutant mice were allowed to have longer intervals between sessions. Deficits in radial maze learning could also be corrected by providing less challenging pretraining. Bianchi et al. (2009) hypothesized that an intact reserve pool of synaptic vesicles is necessary for memory processing under challenging conditions in mice.

▼ ALLELIC VARIANTS ( 4 Selected Examples):

.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 41
GDI1, LEU92PRO
In the family reported by Hamel et al. (1996) with X-linked nonspecific intellectual developmental disorder linked to Xq28 (XLID41; 300849), D'Adamo et al. (1997) identified a T-to-C transition in the GDI1 cDNA, resulting in a leu92-to-pro (L92P) substitution.

.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 41
GDI1, ARG70TER
In affected members of the family with X-linked intellectual developmental disorder (XLID41; 300849) reported by Des Portes et al. (1997), D'Adamo et al. (1997) identified a 366C-T transition in the GDI1 gene, resulting in an arg70-to-ter (R70X) substitution. D'Adamo et al. (1998) speculated that the truncated message could lead to synthesis of a peptide of 69 amino acids, which would likely be unstable and degraded. Moderate to severe mental retardation was found in 7 males and milder intellectual impairment in 2 females, without any specific clinical, radiologic, or biologic features.

.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 41
GDI1, ARG423PRO
In affected members of a large French family with X-linked intellectual developmental disorder (XLID41; 300849), Bienvenu et al. (1998) identified a 1426G-C transversion in the GDI1 gene, resulting in an arg423-to-pro (R423P) substitution.

.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED 41
GDI1, 2-BP DEL, 1185AG
In affected members of a multigenerational German family in which 9 males had nonsyndromic X-linked intellectual developmental disorder (XLID41; 300849), Strobl-Wildemann et al. (2011) identified a 2-bp deletion (1185delAG) in exon 10 of the GDI1 gene, resulting in a frameshift and premature termination. The proband was noted to have absence seizures at age 12, a small pointed chin, and crowded teeth, but major dysmorphic features were not present and no other patients had dysmorphic features. Two of 4 female carriers had learning disabilities, and 1 also had attention-deficit disorder.

Tags: Xq28