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HGNC Approved Gene Symbol: RAP1GDS1
Cytogenetic location: 4q23 Genomic coordinates (GRCh38): 4:98,261,384-98,443,858 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q23 | Alfadhel syndrome | 620655 | Autosomal recessive | 3 |
The smg GDP dissociation stimulator (smgGDS) protein is a stimulatory GDP/GTP exchange protein with GTPase activity (Riess et al., 1993).
By screening a human brain cDNA library with bovine Rap1gds1 cDNA, Kikuchi et al. (1992) cloned RAP1GDS1, which encodes a 558-amino acid protein with a calculated molecular mass of 61.1 kD. Human RAP1GDS1 shares 96% amino acid identity with its bovine homolog. The product of the RAP1GDS1 gene, usually referred to as smgGDS, has guanine nucleotide exchange factor (GEF) activity (Mizuno et al., 1991). RAP1GDS1 stimulates the GDP/GTP exchange reaction of a group of small G proteins by stimulating dissociation of GDP from the subsequent binding of GTP to each small G protein.
Riess et al. (1993) found that the 3-prime end of the cDNA encoding the smgGDS protein shares 100% homology with the previously published EST sequence mapped to chromosome 4 by Durkin et al. (1992) and Polymeropoulos et al. (1992). Using a mapping panel of rodent/human somatic cell hybrids containing different parts of chromosome 4, Riess et al. (1993) refined the localization to chromosome 4q21-q25. They pointed out that this localization falls in a region of allele loss in primary hepatocellular carcinoma.
Hussey et al. (1999) identified the breakpoint genes of the translocation t(4;11)(q21;p15) that occurred in a case of adult T-cell acute lymphocytic leukemia (T-ALL). By analysis of somatic cell hybrids, they showed that the chromosome 11 breakpoint occurred within the NUP98 gene (601021), which is rearranged in several acute myeloid leukemia translocations. Using 3-prime RACE, Hussey et al. (1999) identified the fusion partner of NUP98 as RAP1GDS1. This was the first report of the involvement of RAP1GDS1 in any malignancy. In the fusion transcript, which the authors referred to as NRG, the 5-prime end of the NUP98 gene was joined in-frame to the coding region of the RAP1GDS1 gene. This joined the FG repeat-rich region of NUP98 to RAP1GDS1, which largely consists of tandem armadillo repeats. Hussey et al. (1999) found that the NRG fusion maintained the reading frame of RAP1GDS1. The RAP1GDS1 sequence in NRG started at nucleotide 5 of the coding sequence. The methionine and the first G of the codon for aspartic acid were lost. However, the first aspartic acid was retained in the fusion protein, because the last base of NUP98 exon B is a G. Hussey et al. (1999) showed that this translocation is recurrent in T-ALL.
In 4 male patients from 2 unrelated consanguineous Saudi Arabian families with Alfadhel syndrome (AFDL; 620655), Asiri et al. (2020) identified a homozygous splice site mutation in the RAP1GDS1 gene (179502.0001). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families.
Bertoli-Avella et al. (2021) reported 4 patients from consanguineous families with Alfadhel syndrome and homozygous mutations in the RAP1GDS1 gene. Bertoli-Avella (2023) clarified that patients 22 and 23 in their table 1 were females in whom Bertoli-Avella et al. (2021) had identified the mutations (179502.0001 and 179502.0002, respectively) and that patients 24 and 25 were the patients previously reported by Asiri et al. (2020).
In 4 male patients from 2 unrelated consanguineous Saudi Arabian families with Alfadhel syndrome (AFDL; 620655), Asiri et al. (2020) identified a homozygous G-to-A transition in intron 12 of the RAP1GDS1 gene (c.1444-1G-A, NM_00100426.2), resulting in a splice site alteration. The variant, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. It was not present in the dbSNP, 1000 Genomes Project, ExAC, or gnomAD databases. Analysis of patient cells showed that the variant caused the skipping of exon 13 and resulted in reduced mRNA levels. Additional functional studies were not performed.
Bertoli-Avella et al. (2021) reported a patient (patient 22) from a consanguineous family with Alfadhel syndrome who was homozygous for the c.1444-1G-A splice site mutation in the RAP1GDS1 gene. Bertoli-Avella (2023) clarified that patient 22 was a female in whom they had identified the mutation.
Bertoli-Avella et al. (2021) reported a patient (patient 23) from a consanguineous family with Alfadhel syndrome (AFDL; 620655) who was homozygous for a 1-bp deletion (c.83delT, NM_001100426.1) in the RAP1GDS1 gene, resulting in a frameshift (Leu28fs). Bertoli-Avella (2023) clarified that patient 23 was a female in whom they had identified the mutation.
Asiri, A., Aloyouni, E., Umair, M., Alyafee, Y., Al Tuwaijri, A., Alhamoudi, K. M., Almuzzaini, B., Al Baz, A., Alwadaani, D., Nashabat, M., Alfadhel, M. Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay. Ann. Clin. Transl. Neurol. 7: 956-964, 2020. [PubMed: 32431071] [Full Text: https://doi.org/10.1002/acn3.51059]
Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others. Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders. Genet. Med. 23: 1551-1568, 2021. [PubMed: 33875846] [Full Text: https://doi.org/10.1038/s41436-021-01159-0]
Bertoli-Avella, A. M. Personal Communication. Rostock, Germany 12/1/2023.
Durkin, A. S., Maglott, D. R., Nierman, W. C. Chromosomal assignment of 38 human brain expressed sequence tags (ESTs) by analyzing fluorescently labeled PCR products from hybrid cell panels. Genomics 14: 808-810, 1992. [PubMed: 1427913] [Full Text: https://doi.org/10.1016/s0888-7543(05)80194-6]
Hussey, D. J., Nicola, M., Moore, S., Peters, G. B., Dobrovic, A. The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 94: 2072-2079, 1999. [PubMed: 10477737]
Kikuchi, A., Kaibuchi, K., Hori, Y., Nonaka, H., Sakoda, T., Kawamura, M., Mizuno, T., Takai, Y. Molecular cloning of the human cDNA for a stimulatory GDP/GTP exchange protein for c-Ki-ras p21 and smg p21. Oncogene 7: 289-293, 1992. [PubMed: 1549351]
Mizuno, T., Kaibuchi, K., Yamamoto, T., Kawamura, M., Sakoda, T., Fujioka, H., Matsuura, Y., Takai, Y. A stimulatory GDP/GTP exchange protein for smg p21 is active on the post-translationally processed form of c-Ki-ras p21 and rhoA p21. Proc. Nat. Acad. Sci. 88: 6442-6446, 1991. [PubMed: 1907371] [Full Text: https://doi.org/10.1073/pnas.88.15.6442]
Polymeropoulos, M. H., Xiao, H., Glodek, A., Gorski, M., Adams, M. D., Moreno, R. F., Fitzgerald, M. G., Venter, J. C., Merril, C. R. Chromosomal assignment of 46 brain cDNAs. Genomics 12: 492-496, 1992. [PubMed: 1559700] [Full Text: https://doi.org/10.1016/0888-7543(92)90439-y]
Riess, O., Epplen, C., Siedlaczck, I., Epplen, J. T. Chromosomal assignment of the human smg GDP dissociation stimulator gene to human chromosome 4q21-q25. Hum. Genet. 92: 629-630, 1993. [PubMed: 8262526] [Full Text: https://doi.org/10.1007/BF00420952]