HGNC Approved Gene Symbol: RAB18
Cytogenetic location: 10p12.1 Genomic coordinates (GRCh38) : 10:27,504,304-27,542,239 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p12.1 | Warburg micro syndrome 3 | 614222 | Autosomal recessive | 3 |
Rab proteins comprise a complex family of small GTPases involved in the regulation of intracellular membrane trafficking and reorganization. Rab18 inhibits secretory activity in vertebrate neuroendocrine cells (Vazquez-Martinez et al., 2007).
By stimulating umbilical vein endothelial cells (HUVEC) with histamine and differential display gene expression analysis, Schafer et al. (2000) isolated a cDNA encoding RAB18. The deduced 206-amino acid protein shares 98%, 92%, and 85% identity with the mouse, snail, and worm sequences, respectively. RAB18 contains totally conserved phosphate/Mg(2+)-binding motifs and guanine-binding motifs as well as somewhat variable organelle-targeting regions. Northern blot analysis detected 2.5- and 1.0-kb transcripts in endothelial cells but not in smooth muscle cells or leukocytes. RT-PCR analysis suggested ubiquitous expression, which HPLC analysis determined to be strongest in heart, kidney, pancreas, lung, and liver, with weak expression in brain, placenta, and skeletal muscle.
Schafer et al. (2000) reported that stimulation of polarized HUVEC or nonpolarized mononuclear cells with histamine showed a significant time- and dose-dependent increase of RAB18 transcript in both cell types, suggesting a possible role for Rab proteins in inflammation.
Vazquez-Martinez et al. (2007) found that Rab18 localized to the cytosol in rat PC12 adrenal chromaffin cells and AtT20 mouse pituitary corticotropes. However, Rab18 associated with a subpopulation of secretory granules after stimulation of the regulated secretory pathway and subsequently relocalized to the cell surface. A dominant-inactive rat Rab18 mutant distributed diffusely in the cytosol, whereas a dominant-active rat Rab18 mutant predominantly associated with secretory granules. Interaction with Rab18 slowed secretory granule movement and inhibited secretory activity of PC12 and AtT20 cells in response to stimulatory challenges. Immunoelectron microscopy of normal frog pituitary melanotropes showed an inverse correlation between Rab18 protein content and secretory activity. Vazquez-Martinez et al. (2007) concluded that RAB18 acts as a negative regulator of secretory activity by impairing secretory granule transport.
McMurtrie et al. (1997) mapped the mouse Rab18 gene to chromosome 18.
Hartz (2009) mapped the RAB18 gene to chromosome 10p12.1 based on an alignment of the RAB18 sequence (GenBank AA216667) with the genomic sequence (GRCh37).
In affected members of 5 large consanguineous families, 4 Pakistani and 1 Turkish, segregating Warburg Micro syndrome (WARBM3; 614222), Bem et al. (2011) identified homozygous loss-of-function mutations in the RAB18 gene (602207.0001 and 602207.0002, respectively). Direct sequencing for RAB18 mutations in 58 additional families segregating Warburg Micro syndrome detected compound heterozygous mutations (602207.0003-602207.0004) in affected sibs of 1 family. Bem et al. (2011) performed nucleotide-binding assays and showed that although RAB18 bound GDP and GTP comparably to other RABs (RAB5A, 179512; RAB35, 604199), the RAB18 L24Q (602207.0001) and R93del (602207.0003) mutant proteins did not bind detectable levels of either GDP or GTP and are therefore functionally null. Bem et al. (2011) noted that the pathogenicity of these mutations could be explained by their lack of guanosine nucleotide binding because, as for other RAB proteins, this is a prerequisite for correct subcellular localization and function.
In a 4-year-old Egyptian girl with 'classic' Warburg Micro syndrome, Handley et al. (2013) identified homozygosity for a missense mutation in the RAB18 gene (T95R; 602207.0005).
Bem et al. (2011) investigated the effect of knockdown of rab18 in zebrafish to establish whether rab18 has a conserved role in brain and eye development. The most common abnormalities observed at 3 days post-fertilization in both the rab18a and rab18b morphants were microphthalmia, microcephaly, pericardial edema, delayed jaw formation, a reduced overall body size, and a general developmental delay. Further characterization of the rab18b eye phenotype revealed that the rab18b morphants had delayed retinal development and abnormal retinal lamination, residual nucleated lens fiber cells, widely open choroid fissure, and microphthalmia at day 3. To assess the specificity of the rab18b phenotype, Bem et al. (2011) conducted a rescue experiment by synthesizing rab18b mRNA. Partial rescue of the eye defects, pericardial edema, and overall developmental delay was observed at 3 days.
In affected members of 4 large consanguineous Pakistani families segregating Warburg Micro syndrome-3 (WARBM3; 614222), Bem et al. (2011) identified a homozygous founder mutation in the RAB18 gene: a 71T-A transition resulting in a leu24-to-gln (L24Q) substitution at a highly conserved residue within the alpha-1 helical domain. Nucleotide-binding assays demonstrated that the L24Q mutant did not bind detectable levels of either GDP or GTP and was thus functionally null.
In 2 affected sibs in a consanguineous Turkish family segregating Warburg Micro syndrome-3 (WARBM3; 614222), Bem et al. (2011) identified a homozygous exon 2 deletion predicted to result in a frameshift. The parents were heterozygous for the deletion.
In an affected sister and brother with Warburg Micro syndrome-3 (WARBM3; 614222), originally described by Graham et al. (2004), Bem et al. (2011) identified compound heterozygous mutations in the RAB18 gene: a 3-bp deletion (277_279del) resulting in deletion of arginine-93 (R93del), and an antitermination mutation, a 619T-C transition resulting in a ter207-to-gln (X207Q; 602207.0004) substitution, predicted to extend RAB18 by 20 amino acids (X207QextTer20) and thus abolish C-terminal prenylation and membrane targeting. In addition, nucleotide-binding assays demonstrated that the R93del mutant did not bind detectable levels of either GDP or GTP and was thus functionally null. Bem et al. (2011) stated that the sibs from this family were the oldest known children with WARBM syndrome at ages 21 and 23 years, respectively. Both had severe intractable epilepsy with myoclonic seizures from an early age, and their brain MRIs showed bilateral frontal polymicrogyria and thinning of the corpus callosum. A nerve conduction study in the boy was markedly abnormal due to severe loss of neurons, suggesting an axonal peripheral neuropathy.
For discussion of the ter207-to-gln (X207Q) mutation in the RAB18 gene that was found in compound heterozygous state in a brother and sister with Warburg Micro syndrome-3 (WARBM3; 614222) by Bem et al. (2011), see 602207.0003.
In a 4-year-old Egyptian girl with Warburg Micro syndrome-3 (WARBM3; 614222), Handley et al. (2013) identified homozygosity for a c.284C-G transversion in exon 5 of the RAB18 gene, resulting in a thr95-to-arg (T95R) substitution at a conserved residue within the alpha-3 helix. The mutation segregated with disease in the family and was not present in 400 control chromosomes. Handley et al. (2013) noted that the patient exhibited all the features of 'classic' Warburg Micro syndrome.
Bem, D., Yoshimura, S.-I., Nunes-Bastos, R., Bond, F. C., Kurian, M. A., Rahman, F., Handley, M. T. W., Hadzhiev, Y., Masood, I., Straatman-Iwanowska, A. A., Cullinane, A. R., McNeill, A., and 15 others. Loss-of-function mutations in RAB18 cause Warburg Micro syndrome. Am. J. Hum. Genet. 88: 499-507, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 678 only, 2011. [PubMed: 21473985] [Full Text: https://doi.org/10.1016/j.ajhg.2011.03.012]
Graham, J. M., Jr., Hennekam, R., Dobyns, W. B., Roeder, E., Busch, D. MICRO syndrome: an entity distinct from COFS syndrome. Am. J. Med. Genet. 128A: 235-245, 2004. [PubMed: 15216543] [Full Text: https://doi.org/10.1002/ajmg.a.30060]
Handley, M. T., Morris-Rosendahl, D. J., Brown, S., Macdonald, F., Hardy, C., Bem, D., Carpanini, S. M., Borck, G., Martorell, L., Izzi, C., Faravelli, F., Accorsi, P., and 23 others. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in Warburg Micro syndrome and Martsolf syndrome. Hum. Mutat. 34: 686-696, 2013. [PubMed: 23420520] [Full Text: https://doi.org/10.1002/humu.22296]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/28/2009.
McMurtrie, E. B., Barbosa, M. D. F. S., Zerial, M., Kingsmore, S. F. Rab17 and Rab18, small GTPases with specificity for polarized epithelial cells: genetic mapping in the mouse. Genomics 45: 623-625, 1997. [PubMed: 9367688] [Full Text: https://doi.org/10.1006/geno.1997.4959]
Schafer, U., Seibold, S., Schneider, A., Neugebauer, E. Isolation and characterisation of the human rab18 gene after stimulation of endothelial cells with histamine. FEBS Lett. 466: 148-154, 2000. [PubMed: 10648831] [Full Text: https://doi.org/10.1016/s0014-5793(99)01778-0]
Vazquez-Martinez, R., Cruz-Garcia, D., Duran-Prado, M., Peinado, J. R., Castano, J. P., Malagon, M. M. Rab18 inhibits secretory activity in neuroendocrine cells by interacting with secretory granules. Traffic 8: 867-882, 2007. [PubMed: 17488286] [Full Text: https://doi.org/10.1111/j.1600-0854.2007.00570.x]