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SNX3 (Sorting Nexin 3)

Written2019-12Esra Cicek, Ayca Circir Hatil, Merve Oyken, Harun Cingoz, A.Elif Erson-Bensan
Department of Biological Sciences, Middle East Technical University, Ankara/TURKEY,;;;;

Abstract Sorting Nexin 3 (SNX3) gene maps to chromosome 6, minus strand and has 4 exons and 3 introns. There are 3 alternatively spliced isoforms (transcripts). SNX3 is a member of the sorting nexin family. Members of this family generally have BAR domains and phosphoinositide binding regions called the phox (PX) domain, and are involved in intracellular trafficking. Unlike other sorting nexins, SNX3 does not contain a BAR domain. SNX3 protein interacts with phosphatidylinositol-3-phosphates, and is involved in protein trafficking through its role in the retromer complex.

Keywords Sorting Nexin 3, protein trafficking

(Note : for Links provided by Atlas : click)


Alias (NCBI)SDP3
Grd19 (putative golgi membrane protein-sorting protein) 
MCOPS8 (Microphthalmia Syndromic 8)
HGNC (Hugo) SNX3
HGNC Alias symbGrd19
LocusID (NCBI) 8724
Atlas_Id 43757
Location 6q21  [Link to chromosome band 6q21]
Location_base_pair Starts at 108211224 and ends at 108261040 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping SNX3.png]
Local_order From centromere to telomere: OSTM1-AS1, NR2E1, SNX3, RNA5SP212, RNU6-1144P, AFG1L, RPL36AP24.
  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.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Note SNX3 gene consists of 4 exons and 3 introns. The gene maps to 6q21 and is 49,819 kb long (NCBI Reference Sequence: NC_000006.12 : 108211217-108261260). Highlighted in red is protein coding sequence from exons 1-4.
  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 SNX3 gene is 49,819 kb long and is on the minus strand. SNX3 gene has 4 exons.
Transcription SNX3 produces 4 coding transcripts (1755 bp, 1072 bp, 890 bp and 1537 bp) and there is non-sense mediated decay for a transcript (1537 bp) . Alternative polyadenylation (APA) also creates 2 different isoforms which has short (636 bp) or long (934 bp) untranslated regions (UTRs) (Akman, 2015).
Pseudogene There are 2 pseudogenes of SNX3 which are: SNX3P1Y (sorting nexin 3 pseudogene 1 Y-linked) on chromosome Y and SNX3P1X (sorting nexin 3 pseudogene 1 X-linked) on X chromosome (NCBI, 2018). There is no data available for SNX3P1Y expression. There are RNAseq data results showing SNX3P1X is expressed in blood, brain, cortex, tibial nerve, artery, thyroid, breast, ovary and testis (


Note SNX3 belongs to Sorting Nexins family consisting of more than 30 members (P.J. Cullen, 2008). SNX family members are classified according to their domain structures. Members of sorting nexins have a combination of the following domains: Bin/Rvs/Amphiphysin domain (BAR), Phox homology domain (PX), 4.1/Ezrin/Radixin/Moesin-like domain (FERM), PXA (PX-associated domain A), RGS (Regulator of G-protein signaling), PXC (PX- associated domain C) and MIT (microtubule-interacting and trafficking molecule domain) (R.D. Teasdale, 2012). SNX3 has only the PX domain.
  Figure 3. SNX3 consists of only the PX domain.
Description SNX3 is a small protein of 162 amino acids. Molecular weight of the protein is 18,762 Da.
Expression SNX3 is expressed in brain, eye, endocrine tissues, lung, proximal digestive tract, gastrointestinal tract, liver and gallbladder, pancreas, kidney and urinary bladder, male tissues, female tissues, muscle tissues, adipose and soft tissue, skin, bone marrow and lymphoid tissues and blood. (The Human Protein Atlas,
Localisation SNX3 protein is mostly localized to the endosomes with the retromer complex (M. Harterink, 2011).
Function SNX3 functions within the retromer complex. Among other members of the nexins, only SNX3 is indispensable for recognition and recycling of WLS (Wntless) in Drosophila (P. Zhang, 2011). SNX3 is required for the binding of VPS26 and VPS35 association complex to endosomal membranes (M. Lucas, 2016). For efficient recruitment of retromer proteins to the endosomes, SNX3 binding to PI3Ps of endosomes through its PX domain. RAB7A GTPase is also recruited to the endosome. Consequently, VPS35, VPS26 and VPS29 trimer interacts with the endosome. SNX3 almost functions as a bridge by interacting with the PI3Ps and the VPS trimer. Binding of retromer to SNX3 causes a conformational change on retromer complex, which creates a binding surface for cargo proteins (M. Gallon, 2015).
Homology The SNX3 gene is conserved among species such as chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, frog, zebrafish and yeast.(NCBI).


Note A de novo reciprocal t(6;13)(q21;q12) translocation was detected in a patient with microcephaly, microphthalmia, ectrodactyly, and prognathism (MMEP) and mental retardation. Gene mapping at the site of the breakpoints showed that the translocation breakpoint does not appear to disrupt any gene on chromosome 13, but does disrupt SNX3 gene on chromosome 6q21 (Ververoot et al., 2002).
There are a mutations reported for SNX3 in bladder urothelial carcinoma, breast invasive ductal carcinoma, breast invasive lobular carcinoma, colon adenocarcinoma, cutaneous melanoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, papillary renal cell carcinoma, serous ovarian cancer, tubular stomach adenocarcinoma, uterine endometrioid carcinoma (cBioPortal database) (Cerami et al., 2012; Gao et al., 2013).

Implicated in

Note SNX3 has been implicated in diverse diseases.
Entity Split Hand/Foot Malformation (SHFM)
Note SNX3 locus has been implicated to be a possibly important region for SHFM (Duijf, 2003; Braverman, 1993; Gurrieri, 1995; Correa-Cerro, 1996). 6q21 region is also associated with some other malformations like microcephaly, microphthalmia, ectrodactyly and prognathism (Duijf et.el., 2003 and Vervoort, 2002).
Entity MMEP (Microcephaly, microphthalmia, ectrodactyly and prognathism)
Note SNX3 disruption on 6q21 was reported in a patient with MMEP and t(6;13)(q21;q12) but SNX3 mutations were not identified in other MMEP patients, which may suggest involvement of other genes (Vervoort, 2002).
Entity Autosomal Dominant Polycyctic Kidney Disease (ADPKD).
Note Polycystin-1 ( PKD1) and Polycystin-2 ( PKD2) are plasma membrane receptor-ion channel proteins implicated in ADPKD. SNX3 has a role in endocytosis of PKD2. It was reported that compounds that downregulate SNX3 expression or which inhibit its function could have therapeutic benefits for ADPKD patients. (Feng et al.,2017).
Entity Epidermoid Carcinoma
Note SNX3 has a role in endosomal trafficking of TFRC (transferrin receptor) (Chen et al., 2013). Aspirin is suggested to regulate the recycling of TFRC and possibly EGFR in epidermoid carcinoma cell lines (A-431) by delaying their recycling and causing their accumulation in early endosomes (Chiow et al., 2012).
Entity Acute Lymphoblastic Leukemia
Note Dexamethasone (DEXA) is a frequently preferred chemotherapeutic drug for childhood acute lymphoblastic leukemia (ALL) patients, however, drug resistance is a problem. Proteomic studies revealed that SNX3 is expressed differentially between DEXA treated DEXA- resistant cell line (REH) and non-DEXA treated REH. In REH cells, SNX3 expression is down-regulated. Additionally, both in high risk and standard risk group ALL patients, SNX3 downregulation is observed when compared to normal control group. Downregulation of SNX3 may be associated with both chemoresistance and tumorigenesis (Dehghan-Nayeri et al., 2017).
Entity Alzheimier Disease
Note Neurotoxic amyloid β peptide (Aβ) with the processing of amyloid precursor protein ( APP) by proteolytic cleavage has the leading role in Alzheimier disease (AD) pathogenesis (Vardarajan, 2012). Retromer complex including SNX3 provides proper trafficking of APP, which is necessary to prevent abnormal production of Aβ peptide. It was reported that SNX3 has AD related SNPs. Overexpression of SNX3 in HEK293T showed reduction in the secreted Aβ level. Regulation of Aβ peptide with controlling APP may make SNX3 a candidate for AD treatment (Xu, 2018).
Entity Parkinson's Disease
Note Alpha-synuclein ( SNCA) protein has a role in the iron metabolism and expression. High expression level of alpha-synuclein in dopaminergic neurons causes Parkinson's Disease. In yeast, Fet3/Ftr1 complex has role in external iron intake. When the external iron concentration is low, interaction of Ftr1 C-terminus with Snx3-retromer complex provides retrograde transport of the complex. Under the condition of high external iron concentration, internalized complex is degraded. Interestingly, action of the α-syn mimics the high iron concentration response and leads to degradation of Fet3/Ftr1 via hindering the Snx3 interaction with early endosome and hence, cellular iron homeostasis is disrupted (Patel, 2018).
Entity Anemia
Note SNX3 functions in the recycling of TFRC (transferrin receptor). Knockdown of snx3 in zebrafish embryos results in intensive anemia. Consistently, silencing of Snx3 in mouse primary fatal liver cells causes reduced total hemoglobin content (Chen et al., 2013).
Entity Infection
Note SNX3 has a role in Salmonella typhimirium infection in human cells. S.typhimirium is an intracellular pathogen and resides in Salmonella containing vesicles (SCVs) in cell. During infection, SNX3 functions in the tubule formation from the SCVs during Salmonella invasion (Braun et al., 2010).


Sorting nexin 3 (SNX3) is a component of a tubular endosomal network induced by Salmonella and involved in maturation of the Salmonella-containing vacuole
Braun V, Wong A, Landekic M, Hong WJ, Grinstein S, Brumell JH
Cell Microbiol 2010 Sep 1;12(9):1352-67
PMID 20482551
The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N
Cancer Discov 2012 May;2(5):401-4
PMID 22588877
Snx3 regulates recycling of the transferrin receptor and iron assimilation
Chen C, Garcia-Santos D, Ishikawa Y, Seguin A, Li L, Fegan KH, Hildick-Smith GJ, Shah DI, Cooney JD, Chen W, King MJ, Yien YY, Schultz IJ, Anderson H, Dalton AJ, Freedman ML, Kingsley PD, Palis J, Hattangadi SM, Lodish HF, Ward DM, Kaplan J, Maeda T, Ponka P, Paw BH
Cell Metab 2013 Mar 5;17(3):343-52
PMID 23416069
SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells
Chiow KH, Tan Y, Chua RY, Huang D, Ng ML, Torta F, Wenk MR, Wong SH
Cell Mol Life Sci 2012 May;69(9):1505-21
PMID 22159558
Interstitial deletion 6q16
Correa-Cerro L, Garcíaz-Cruz D, Díaz-Castaños L, Figuera LE, Sanchez-Corona J
2q22 2 in a child with ectrodactyly
PMID 8766142
Endosomal sorting and signalling: an emerging role for sorting nexins
Cullen PJ
Nat Rev Mol Cell Biol 2008 Jul;9(7):574-82
PMID 18523436
Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia
Dehghan-Nayeri N, Rezaei-Tavirani M, Omrani MD, Gharehbaghian A, Goudarzi Pour K, Eshghi P
J Cell Commun Signal 2017 Jun;11(2):137-145
PMID 27778231
Pathogenesis of split-hand/split-foot malformation
Duijf PH, van Bokhoven H, Brunner HG
Hum Mol Genet 2003 Apr 1;12 Spec No 1:R51-60
PMID 12668597
The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex
Feng S, Streets AJ, Nesin V, Tran U, Nie H, Onopiuk M, Wessely O, Tsiokas L, Ong ACM
J Am Soc Nephrol 2017 Oct;28(10):2973-2984
PMID 28620080
Retromer and sorting nexins in endosomal sorting
Gallon M, Cullen PJ
Biochem Soc Trans 2015 Feb;43(1):33-47
PMID 25619244
Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N
Sci Signal 2013 Apr 2;6(269):pl1
PMID 23550210
Ulnar ray defect in an infant with a 6q21;7q31
Gurrieri F, Cammarata M, Avarello RM, Genuardi M, Pomponi MG, Neri G, Giuffrè L
2 translocation: further evidence for the existence of a limb defect gene in 6q21 Am J Med Genet
PMID 7726229
A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion
Harterink M, Port F, Lorenowicz MJ, McGough IJ, Silhankova M, Betist MC, van Weering JRT, van Heesbeen RGHP, Middelkoop TC, Basler K, Cullen PJ, Korswagen HC
Nat Cell Biol 2011 Jul 3;13(8):914-923
PMID 21725319
Structural Mechanism for Cargo Recognition by the Retromer Complex
Lucas M, Gershlick DC, Vidaurrazaga A, Rojas AL, Bonifacino JS, Hierro A
Cell 2016 Dec 1;167(6):1623-1635
PMID 27889239
Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S
Patel D, Xu C, Nagarajan S, Liu Z, Hemphill WO, Shi R, Uversky VN, Caldwell GA, Caldwell KA, Witt SN
cerevisiae and C elegans models of Parkinson's disease
PMID 29452354
The use and misuse of thyroid hormone
Roti E, Minelli R, Gardini E, Braverman LE
Endocr Rev 1993 Aug;14(4):401-23
PMID 8223339
Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease
Teasdale RD, Collins BM
Biochem J 2012 Jan 1;441(1):39-59
PMID 22168438
Identification of Alzheimer disease-associated variants in genes that regulate retromer function
Vardarajan BN, Bruesegem SY, Harbour ME, Inzelberg R, Friedland R, St George-Hyslop P, Seaman MN, Farrer LA
Neurobiol Aging 2012 Sep;33(9):2231
PMID 22673115
Mutations of RPGR in X-linked retinitis pigmentosa (RP3)
Vervoort R, Wright AF
Hum Mutat 2002 May;19(5):486-500
PMID 11968081
Sorting nexin 3 (SNX3) is disrupted in a patient with a translocation t(6;13)(q21;q12) and microcephaly, microphthalmia, ectrodactyly, prognathism (MMEP) phenotype
Vervoort VS, Viljoen D, Smart R, Suthers G, DuPont BR, Abbott A, Schwartz CE
J Med Genet 2002 Dec;39(12):893-9
PMID 12471201
Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein
Xu S, Nigam SM, Brodin L
Neurodegener Dis 2018;18(1):26-37
PMID 29414832
SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless
Zhang P, Wu Y, Belenkaya TY, Lin X
Cell Res 2011 Dec;21(12):1677-90
PMID 22041890


This paper should be referenced as such :
Esra Cicek, Ayca Circir Hatil, Merve Oyken, Harun Cingoz, A Elif Erson-Bensan
SNX3 (Sorting Nexin 3)
Atlas Genet Cytogenet Oncol Haematol. 2020;24(9):333-336.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Del(6q) in Chronic lymphocytic leukaemia (CLL)

External links

HGNC (Hugo)SNX3   11174
Entrez_Gene (NCBI)SNX3    sorting nexin 3
AliasesGrd19; MCOPS8; SDP3
GeneCards (Weizmann)SNX3
Ensembl hg19 (Hinxton)ENSG00000112335 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000112335 [Gene_View]  ENSG00000112335 [Sequence]  chr6:108211224-108261040 [Contig_View]  SNX3 [Vega]
ICGC DataPortalENSG00000112335
TCGA cBioPortalSNX3
AceView (NCBI)SNX3
Genatlas (Paris)SNX3
SOURCE (Princeton)SNX3
Genetics Home Reference (NIH)SNX3
Genomic and cartography
GoldenPath hg38 (UCSC)SNX3  -     chr6:108211224-108261040 -  6q21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)SNX3  -     6q21   [Description]    (hg19-Feb_2009)
GoldenPathSNX3 - 6q21 [CytoView hg19]  SNX3 - 6q21 [CytoView hg38]
Genome Data Viewer NCBISNX3 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AB047360 AF034546 AF062483 AI921483 AK289476
RefSeq transcript (Entrez)NM_001300928 NM_001300929 NM_003795 NM_152827 NM_152828
Consensus coding sequences : CCDS (NCBI)SNX3
Gene ExpressionSNX3 [ NCBI-GEO ]   SNX3 [ EBI - ARRAY_EXPRESS ]   SNX3 [ SEEK ]   SNX3 [ MEM ]
Gene Expression Viewer (FireBrowse)SNX3 [ Firebrowse - Broad ]
GenevisibleExpression of SNX3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8724
GTEX Portal (Tissue expression)SNX3
Human Protein AtlasENSG00000112335-SNX3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)SNX3
Human Protein Atlas [tissue]ENSG00000112335-SNX3 [tissue]
Protein Interaction databases
Ontologies - Pathways
PubMed56 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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