SNX3 (Sorting Nexin 3)

2019-12-01   Esra Cicek , Ayca Circir Hatil , Merve Oyken , Harun Cingoz , A.Elif Erson-Bensan 

Department of Biological Sciences, Middle East Technical University, Ankara\\\/TURKEY, esyavuz@metu.edu.tr; cayca@metu.edu.tr; oyken.merve@metu.edu.tr; harun.cingoz@gmail.com; erson@metu.edu.tr

Identity

LOCATION
6q21
IMAGE
Atlas Image
LEGEND
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.
LOCUSID
ALIAS
Grd19,MCOPS8,SDP3

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.

DNA/RNA

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.
Atlas Image
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 et.al., 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 (genecards.org).

Proteins

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.
Atlas Image
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, http://www.proteinatlas.org/).

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).

Mutations

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

Top note
SNX3 has been implicated in diverse diseases.
Entity name
Split Hand/Foot Malformation (SHFM)
Note
SNX3 locus has been implicated to be a possibly important region for SHFM (Duijf et.al., 2003; Braverman et.al., 1993; Gurrieri et.al., 1995; Correa-Cerro et.al., 1996). 6q21 region is also associated with some other malformations like microcephaly, microphthalmia, ectrodactyly and prognathism (Duijf et.el., 2003 and Vervoort et.al., 2002).
Entity name
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 et.al., 2002).
Entity name
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 name
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 name
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 name
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 name
Parkinsons 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 Parkinsons 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 name
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 name
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).

Bibliography

Pubmed IDLast YearTitleAuthors
204825512010Sorting 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 et al
225888772012The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.Cerami E et al
234160692013Snx3 regulates recycling of the transferrin receptor and iron assimilation.Chen C et al
221595582012SNX3-dependent regulation of epidermal growth factor receptor (EGFR) trafficking and degradation by aspirin in epidermoid carcinoma (A-431) cells.Chiow KH et al
87661421996Interstitial deletion 6q16.2q22.2 in a child with ectrodactyly.Correa-Cerro L et al
185234362008Endosomal sorting and signalling: an emerging role for sorting nexins.Cullen PJ et al
277782312017Identification of potential predictive markers of dexamethasone resistance in childhood acute lymphoblastic leukemia.Dehghan-Nayeri N et al
126685972003Pathogenesis of split-hand/split-foot malformation.Duijf PH et al
286200802017The Sorting Nexin 3 Retromer Pathway Regulates the Cell Surface Localization and Activity of a Wnt-Activated Polycystin Channel Complex.Feng S et al
256192442015Retromer and sorting nexins in endosomal sorting.Gallon M et al
235502102013Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.Gao J et al
77262291995Ulnar ray defect in an infant with a 6q21;7q31.2 translocation: further evidence for the existence of a limb defect gene in 6q21.Gurrieri F et al
217253192011A SNX3-dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion.Harterink M et al
278892392016Structural Mechanism for Cargo Recognition by the Retromer Complex.Lucas M et al
294523542018Alpha-synuclein inhibits Snx3-retromer-mediated retrograde recycling of iron transporters in S. cerevisiae and C. elegans models of Parkinson's disease.Patel D et al
82233391993The use and misuse of thyroid hormone.Roti E et al
221684382012Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease.Teasdale RD et al
226731152012Identification of Alzheimer disease-associated variants in genes that regulate retromer function.Vardarajan BN et al
119680812002Mutations of RPGR in X-linked retinitis pigmentosa (RP3).Vervoort R et al
124712012002Sorting 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 et al
294148322018Overexpression of SNX3 Decreases Amyloid-β Peptide Production by Reducing Internalization of Amyloid Precursor Protein.Xu S et al
220418902011SNX3 controls Wingless/Wnt secretion through regulating retromer-dependent recycling of Wntless.Zhang P et al

Citation

Esra Cicek ; Ayca Circir Hatil ; Merve Oyken ; Harun Cingoz ; A.Elif Erson-Bensan

SNX3 (Sorting Nexin 3)

Atlas Genet Cytogenet Oncol Haematol. 2019-12-01

Online version: http://atlasgeneticsoncology.org/gene/43757/snx3