Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Gene Section Review SNX3 (Sorting Nexin 3) Esra Cicek, Ayca Circir Hatil, Merve Oyken, Harun Cingoz, A.Elif Erson-Bensan Department of Biological Sciences, Middle East Technical University, Ankara/TURKEY, [email protected]; [email protected]; [email protected]; [email protected]; [email protected] Published in Atlas Database: December 2019 Online updated version : http://AtlasGeneticsOncology.org/Genes/SNX3ID43757ch6q21.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70783/12-2019-SNX3ID43757ch6q21.pdf DOI: 10.4267/2042/70783 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Identity Sorting Nexin 3 (SNX3) gene maps to chromosome Other names: SDP3; Grd19; MCOPS8 6, minus strand and has 4 exons and 3 introns. There HGNC (Hugo): SNX3 are 3 alternatively spliced isoforms (transcripts). Location: 6q21 SNX3 is a member of the sorting nexin family. Members of this family generally have BAR Local order domains and phosphoinositide binding regions From centromere to telomere: OSTM1-AS1, called the phox (PX) domain, and are involved in NR2E1, SNX3, RNA5SP212, RNU6-1144P, intracellular trafficking. Unlike other sorting nexins, AFG1L, RPL36AP24. SNX3 does not contain a BAR domain. SNX3 protein interacts with phosphatidylinositol-3- DNA/RNA phosphates, and is involved in protein trafficking SNX3 gene consists of 4 exons and 3 introns. The through its role in the retromer complex. gene maps to 6q21 and is 49,819 kb long (NCBI Keywords Reference Sequence: NC_000006.12 : 108211217- Sorting Nexin 3, protein trafficking 108261260). Highlighted in red is protein coding sequence from exons 1-4. Figure 1. Local order of SNX3 is shown together with leading and subsequent genes on chromosome 6. The direction of arrows indicates transcriptional direction on the chromosome and arrow sizes approximate gene sizes. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(9) 333 PARP1 (poly(ADP-ribose) polymerase 1) Tunçer S, Kavak K Figure 2. SNX3 gene has 4 exons and 3 introns. Numbers indicate the exons. Red boxes represents exons/ protein- coding regions and blue boxes represent untranslated regions. Description Description SNX3 gene is 49,819 kb long and is on the minus SNX3 is a small protein of 162 amino acids. strand. SNX3 gene has 4 exons. Molecular weight of the protein is 18,762 Da. Transcription Expression SNX3 produces 4 coding transcripts (1755 bp, 1072 SNX3 is expressed in brain, eye, endocrine tissues, bp, 890 bp and 1537 bp) and there is non-sense lung, proximal digestive tract, gastrointestinal tract, mediated decay for a transcript (1537 bp). liver and gallbladder, pancreas, kidney and urinary Alternative polyadenylation (APA) also creates 2 bladder, male tissues, female tissues, muscle tissues, different isoforms which has short (636 bp) or long adipose and soft tissue, skin, bone marrow and (934 bp) untranslated regions (UTRs) (Akman et.al., lymphoid tissues and blood. (The Human Protein 2015). Atlas, http://www.proteinatlas.org/). Pseudogene Localisation There are 2 pseudogenes of SNX3 which are: SNX3 protein is mostly localized to the endosomes SNX3P1Y (sorting nexin 3 pseudogene 1 Y-linked) with the retromer complex (M. Harterink, 2011). on chromosome Y and SNX3P1X (sorting nexin 3 Function pseudogene 1 X-linked) on X chromosome (NCBI, 2018). SNX3 functions within the retromer complex. There is no data available for SNX3P1Y expression. Among other members of the nexins, only SNX3 is There are RNAseq data results showing SNX3P1X indispensable for recognition and recycling of WLS is expressed in blood, brain, cortex, tibial nerve, (Wntless) in Drosophila (P. Zhang, 2011). SNX3 is artery, thyroid, breast, ovary and testis required for the binding of VPS26 and VPS35 (genecards.org). association complex to endosomal membranes (M. Lucas, 2016). For efficient recruitment of retromer Protein proteins to the endosomes, SNX3 binding to PI3Ps of endosomes through its PX domain. RAB7A SNX3 belongs to Sorting Nexins family consisting GTPase is also recruited to the endosome. of more than 30 members (P.J. Cullen, 2008). SNX Consequently, VPS35, VPS26 and VPS29 trimer family members are classified according to their interacts with the endosome. SNX3 almost functions domain structures. Members of sorting nexins have as a bridge by interacting with the PI3Ps and the VPS a combination of the following domains: trimer. Binding of retromer to SNX3 causes a Bin/Rvs/Amphiphysin domain (BAR), Phox conformational change on retromer complex, which homology domain (PX), 4.1/Ezrin/Radixin/Moesin- creates a binding surface for cargo proteins (M. like domain (FERM), PXA (PX-associated domain Gallon, 2015). A), RGS (Regulator of G-protein signaling), PXC (PX- associated domain C) and MIT (microtubule- Homology interacting and trafficking molecule domain) (R.D. The SNX3 gene is conserved among species such as Teasdale, 2012). SNX3 has only the PX domain. chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, frog, zebrafish and yeast.(NCBI). Figure 3. SNX3 consists of only the PX domain. Atlas Genet Cytogenet Oncol Haematol. 2020; 24(8) 334 SNX3 (Sorting Nexin 3) Cicek E et al. accumulation in early endosomes (Chiow et al., Mutations 2012). A de novo reciprocal t(6;13)(q21;q12) translocation Acute Lymphoblastic Leukemia was detected in a patient with microcephaly, Dexamethasone (DEXA) is a frequently preferred microphthalmia, ectrodactyly, and prognathism chemotherapeutic drug for childhood acute (MMEP) and mental retardation. Gene mapping at lymphoblastic leukemia (ALL) patients, however, the site of the breakpoints showed that the drug resistance is a problem. Proteomic studies translocation breakpoint does not appear to disrupt revealed that SNX3 is expressed differentially any gene on chromosome 13, but does disrupt SNX3 between DEXA treated DEXA- resistant cell line gene on chromosome 6q21 (Ververoot et al., 2002). (REH) and non-DEXA treated REH. In REH cells, There are a mutations reported for SNX3 in bladder SNX3 expression is down-regulated. Additionally, urothelial carcinoma, breast invasive ductal both in high risk and standard risk group ALL carcinoma, breast invasive lobular carcinoma, colon patients, SNX3 downregulation is observed when adenocarcinoma, cutaneous melanoma, esophageal compared to normal control group. Downregulation squamous cell carcinoma, head and neck squamous of SNX3 may be associated with both cell carcinoma, lung squamous cell carcinoma, chemoresistance and tumorigenesis (Dehghan- papillary renal cell carcinoma, serous ovarian Nayeri et al., 2017). cancer, tubular stomach adenocarcinoma, uterine endometrioid carcinoma (cBioPortal database) Alzheimier Disease (Cerami et al., 2012; Gao et al., 2013). Neurotoxic amyloid β peptide (Aβ) with the processing of amyloid precursor protein ( APP) by Implicated in proteolytic cleavage has the leading role in SNX3 has been implicated in diverse diseases. Alzheimier disease (AD) pathogenesis (Vardarajan, 2012). Retromer complex including SNX3 provides Split Hand/Foot Malformation (SHFM) proper trafficking of APP, which is necessary to SNX3 locus has been implicated to be a possibly prevent abnormal production of Aβ peptide. It was important region for SHFM (Duijf et.al., 2003; reported that SNX3 has AD related SNPs. Braverman et.al., 1993; Gurrieri et.al., 1995; Correa- Overexpression of SNX3 in HEK293T showed Cerro et.al., 1996). 6q21 region is also associated reduction in the secreted Aβ level. Regulation of Aβ with some other malformations like microcephaly, peptide with controlling APP may make SNX3 a microphthalmia, ectrodactyly and prognathism candidate for AD treatment (Xu, 2018). (Duijf et. al., 2003 and Vervoort et.al., 2002). Parkinson's Disease MMEP (Microcephaly, Alpha-synuclein (SNCA) protein has a role in the microphthalmia, ectrodactyly and iron metabolism and expression. High expression prognathism) level of alpha-synuclein in dopaminergic neurons SNX3 disruption on 6q21 was reported in a patient causes Parkinson's disease. with MMEP and t(6;13)(q21;q12) but SNX3 In yeast, Fet3/Ftr1 complex has role in external iron mutations were not identified in other MMEP intake. When the external iron concentration is low, patients, which may suggest involvement of other interaction of Ftr1 C-terminus with Snx3-retromer genes (Vervoort et.al., 2002). complex provides retrograde transport of the complex. Under the condition of high external iron Autosomal Dominant Polycyctic concentration, internalized complex is degraded. Kidney Disease (ADPKD). Interestingly, action of the α-syn mimics the high Polycystin-1 (PKD1) and Polycystin-2 (PKD2) are iron concentration response and leads to degradation plasma membrane receptor-ion channel proteins of Fet3/Ftr1 via hindering the Snx3 interaction with implicated in ADPKD. SNX3 has a role in early endosome and hence, cellular iron homeostasis endocytosis of PKD2. It was reported that is disrupted (Patel, 2018). compounds that downregulate SNX3 expression or Anemia which inhibit its function could have therapeutic benefits for ADPKD patients. (Feng et al.,2017). SNX3 functions in the recycling of TFRC (transferrin receptor). Knockdown of snx3 in Epidermoid Carcinoma zebrafish embryos results in intensive anemia. SNX3 has a role in endosomal trafficking of TFRC