HGNC Approved Gene Symbol: REPS1
Cytogenetic location: 6q24.1 Genomic coordinates (GRCh38) : 6:138,903,493-138,988,253 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q24.1 | ?Neurodegeneration with brain iron accumulation 7 | 617916 | Autosomal recessive | 3 |
The REPS1 gene encodes a protein involved in endocytosis and vesicular transport (summary by Drecourt et al., 2018).
By large-scale sequencing of clones obtained from a human fetal brain cDNA library, followed by database analysis, Xu et al. (2001) identified the human ortholog of mouse Reps1. The deduced 744-amino acid REPS1 protein has a calculated molecular mass of 85 kD. It has a central EPS15 (600051) homology (EH) domain containing 2 EF hand motifs, followed by 2 proline-rich motifs. Mouse and human REPS1 share 83% amino acid identity. Northern blot analysis detected variable expression of an approximately 2.8-kb REPS1 transcript in all 16 human tissues examined, with highest expression in heart and testis.
Cullis et al. (2002) showed that fluorescence-tagged mouse Reps1 colocalized with rat Rab11fip2 (608599) at recycling endosomes in the perinuclear region of transfected NIH3T3 cells.
By yeast 2-hybrid and mutation analyses, Cullis et al. (2002) showed that the isolated EH domain of mouse Reps1 interacted with the NPF motifs of rat Rab11fip2. These 2 proteins appeared to function together in inhibiting the recycling of Egf receptors (EGFR; 131550), but not transferrin receptors (TFRC; 190010). Both Reps1 and Rab11fip2 also coprecipitated with the alpha-adaptin (AP2A1; 601026) subunit of the major clathrin adaptor complex AP2.
Xu et al. (2001) determined that the REPS1 gene contains 20 exons and spans over 44 kb.
By genomic sequence analysis, Xu et al. (2001) mapped the REPS1 gene to chromosome 6q23.1-q24.1.
In 2 sisters, born of unrelated French parents, with neurodegeneration with brain iron accumulation-7 (NBIA7; 617916), Drecourt et al. (2018) identified compound heterozygous missense mutations in the REPS1 gene (V78L, 614825.0001 and A113E, 614825.0002). Both mutations occurred in the EH1 domain, a conserved region that interacts with RALBP1 (605801) to form the endosome recycling compartment. The variants, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls, and wildtype RESP1 was able to return the iron content to control levels. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. Drecourt et al. (2018) concluded that certain forms of NBIA result from defective endosomal recycling and should be regarded as a disorder of cellular trafficking.
In 2 sisters, born of unrelated French parents, with neurodegeneration with brain iron accumulation-7 (NBIA7; 617916), Drecourt et al. (2018) identified compound heterozygous missense mutations in the REPS1 gene: a c.232G-C transversion (c.232G-C, NM_001286611.1), resulting in a val78-to-leu (V78L) substitution, and a c.338C-A transversion, resulting in an ala113-to-glu (A113E; 614825.0002) substitution. Both mutations occurred in the EH1 domain, a conserved region that interacts with RALBP1 (605801) to form the endosome recycling compartment. The variants, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The V78L variant was not found in the dbSNP, Exome Sequencing Project (ESP), or ExAC databases, whereas A113E was found at a low frequency in all 3 databases (0.011% in ExAC and 0.0001 in ESP). Neither variant was found in 200 control chromosomes. Immunoblot analysis detected low amounts of REPS1 in patient fibroblasts.
For discussion of the c.338C-A transversion (c.338C-A, NM_001286611.1) in the RESP1 gene, resulting in an ala113-to-glu (A113E) substitution that was found in compound heterozygous state in 2 sisters with neurodegeneration with brain iron accumulation-7 (NBIA7; 617916) by Drecourt et al. (2018), see 614825.0001.
Cullis, D. N., Philip, B., Baleja, J. D., Feig, L. A. Rab11-FIP2, an adaptor protein connecting cellular components involved in internalization and recycling of epidermal growth factor receptors. J. Biol. Chem. 277: 49158-49166, 2002. [PubMed: 12364336] [Full Text: https://doi.org/10.1074/jbc.M206316200]
Drecourt, A., Babdor, J., Dussiot, M., Petit, F., Goudin, N., Garfa-Traore, M., Habarou, F., Bole-Feysot, C., Nitschke, P., Ottolenghi, C., Metodiev, M. D., Serre, V., Desguerre, I., Boddaert, N., Hermine, O., Munnich, A., Rotig, A. Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 102: 266-277, 2018. [PubMed: 29395073] [Full Text: https://doi.org/10.1016/j.ajhg.2018.01.003]
Xu, J., Zhou, Z., Zeng, L., Huang, Y., Zhao, W., Cheng, C., Xu, M., Xie, Y., Mao, Y. Cloning, expression and characterization of a novel human REPS1 gene. Biochim. Biophys. Acta 1522: 118-121, 2001. [PubMed: 11750063] [Full Text: https://doi.org/10.1016/s0167-4781(01)00310-4]