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Alternative titles; symbolsRAB5-ACTIVATING PROTEIN 6; RAP6RAB5 EXCHANGE FACTOR; GAPEX5KIAA1521HGNC Approved Gene Symbol: GAPVD1Cytogenetic location: 9q33.3 G...

Alternative titles; symbols

  • KIAA1521

HGNC Approved Gene Symbol: GAPVD1

Cytogenetic location: 9q33.3 Genomic coordinates (GRCh38): 9:125,261,793-125,367,206 (from NCBI)

▼ Description
The GAPVD1 gene encodes a protein with both GTPase activating and inactivating domains which acts as a guanine nucleotide exchange factor (GEF) for the RAB5a (179512) GTPase. GAPVD1 also has been described as an endosomal regulator (summary by Hermle et al., 2018).

▼ Cloning and Expression
Hunker et al. (2006) identified a Rab GTPase guanine nucleotide exchange factor (GEF), which they named RAP6 (Rab5-activating protein-6), as a protein of approximately 150 kD that interacted with Rab5a (179512) in HeLa cells. After isolating and characterizing the protein by mass spectrometry, they identified it by database analysis as GAPVD1. The deduced 1,439-amino acid protein has a predicted molecular mass of 158 kD. It contains a C-terminal Vps9-like motif, which is found in other Rab5 GEFs, and an N-terminal RasGAP-like domain (RGD) similar to those found in GAP proteins that specifically interact with Ras proteins. An antibody raised to RAP6 localized the protein to the plasma membrane and intracellular vesicles.

Hermle et al. (2018) found that GAPVD1 was predominantly expressed in the cytosol of podocytes and HEK293T cells, with some N-terminal truncated isoforms localizing to RAB5-positive vesicles. GAPVD1 colocalized completely and partially with ANKFY1 (607927) in HEKS293 cells and podocytes, respectively. Immunoprecipitation studies showed that GAPVD1 also interacts with nephrin (NPHS1; 602716). GAPVD1 and NPHS1 partially colocalized in podocytes and mesangial cells in the glomeruli of newborn rat kidney samples.

▼ Gene Function
Hunker et al. (2006) confirmed that RAP6 binds to Rab5 and Ras through the Vps9 and RGD domains, respectively. Overexpression of RAP6 affected both fluid phase and receptor-mediated endocytosis. Hunker et al. (2006) suggested that RAP6 may play a role in endocytosis by regulating endosome morphology.

Su et al. (2007) studied the same protein, which they called Rab5 exchange factor (GAPEX5), in epidermal growth factor receptor (EGFR; 131550) trafficking and degradation. Depletion of the protein delayed EGFR degradation, whereas overexpression had the reverse effect. Su et al. (2007) proposed that GAPEX5 affects EGFR degradation by mediating receptor ubiquitination through its RGD domain and may be an important mediator of carcinogenesis resulting from mutations in the Ras proteins.

Kitano et al. (2008) found that GAPEX5 is the guanine nucleotide exchange factor essential for activation of RAB5 (179512) during engulfment of apoptotic cells. GAPEX5 was bound to a microtubule tip-associating protein, EB1 (603108), whose depletion inhibited Rab5 activation during phagocytosis. Kitano et al. (2008) therefore proposed a mechanistic model in which the recruitment of GAPEX5 to phagosomes through the microtubule network induces transient RAB5 activation.

▼ Mapping
By database analysis, Hunker et al. (2006) identified the GAPVD1 gene on chromosome 9q33.3.

▼ Molecular Genetics
Associations Pending Confirmation

In 2 unrelated girls, each born of consanguineous parents, with nephrotic syndrome (see, e.g., NPHS1; 256300), Hermle et al. (2018) identified homozygous missense variants in the GAPVD1 gene (L414V and R937Q). The variants, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were present in the heterozygous state at low frequencies in the ExAC and gnomAD databases. The patients were ascertained from a cohort of 665 patients with steroid-resistant nephrotic syndrome who underwent whole-exome sequencing. The unaffected parents of 1 patient (B1391) were each heterozygous for the variant, confirming segregation. Parental DNA was not available for the other patient (A4619), so segregation could not be confirmed. Overexpression of variant GAPVD1 in HEK293 cells showed that the substitutions impaired the binding of GAPVD1 to ANKFY1 (607927) and to NPHS1 (602716). Although both variant proteins showed increased binding to active RAB5, increased RAB5 activity was observed only for R937Q, not L414V. Knockdown of GAPVD1 in podocytes resulted in a reduced migration rate that could be partially rescued by the human variants, suggesting that they are hypomorphic alleles. Knockdown of the orthologous gene (CG1657) in Drosophila nephrocytes caused structural abnormalities of slit diaphragms, impaired endocytosis, and altered trafficking of Nphs1. Hermle et al. (2018) hypothesized that deleterious variants in the GAPVD1 gene adversely impact endocytosis of NPHS1 and alter RAB5 regulation, resulting in impaired function of the podocyte and underlying nephrotic syndrome. One patient had onset of proteinuria at 2 months of age, followed by spontaneous remission at 18 months. The other patient had onset of proteinuria at 18 months of age. Renal biopsy in both patients showed mesangial hypercellularity and podocyte foot process effacement. Both had normal renal function.

Tags: 9q33.3