FAM43A

Located on the long arm of Chromosome 3 at 3q29, FAM43A consists of 2,493 bases; and the translated protein contains a phosphotyrosine interaction domain, putative phosphoinositide binding site and putative peptide binding sites.{{cite web|title=NCBI Protein|url=https://www.ncbi.nlm.nih.gov/protein/NP_710157.2|website=NCBI|publisher=U.S. National Library of Medicine|access-date=February 18, 2018}}

The FAM43A gene has been identified in cDNA screening as a possible cancer development and progression candidate gene.{{cite journal | vauthors = Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L, Zhou X, Li H, Qiu X, Zhong F, He L, Yu J, Yao G, Jiang H, Qian L, Yu Y, Shu H, Chen X, Xu H, Guo M, Pan Z, Chen Y, Ge C, Yang S, Gu J | title = Large-scale cDNA transfection screening for genes related to cancer development and progression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 44 | pages = 15724–9 | date = November 2004 | pmid = 15498874 | pmc = 524842 | doi = 10.1073/pnas.0404089101 | bibcode = 2004PNAS..10115724W | doi-access = free }} Unpublished data from Zhang et al. indicates that FAM43A could possess tumor suppressor function{{cite web|title=FAM43A mRNA page|url=https://www.ncbi.nlm.nih.gov/nuccore/NM_153690.4|website=NCBI|access-date=February 4, 2018}} however the direct interaction is unknown. As well as playing a role in cancer development, FAM43A has been identified as a possible autism spectrum disorder (ASD) candidate gene, with mutations within the upstream single nucleotide polymorphism (SNP) rs789859 correlating with the presentation of ASD and learning disorder; suggesting that this SNP is the promoter region for the downstream FAM43A gene.{{cite journal | vauthors = Baron-Cohen S, Murphy L, Chakrabarti B, Craig I, Mallya U, Lakatošová S, Rehnstrom K, Peltonen L, Wheelwright S, Allison C, Fisher SE, Warrier V | title = A genome wide association study of mathematical ability reveals an association at chromosome 3q29, a locus associated with autism and learning difficulties: a preliminary study | journal = PLOS ONE | volume = 9 | issue = 5 | pages = e96374 | date = 2014 | pmid = 24801482 | pmc = 4011843 | doi = 10.1371/journal.pone.0096374 | bibcode = 2014PLoSO...996374B | doi-access = free }} The 2014 study completed by Baron-Cohen et al. involved the screening of 906 K SNPs within the genome to identify possible candidate genes, with FAM43A being the closest gene to the polymorphism.

FAM43A and paralog FAM43B comprise a specific gene family, and share structural homology with the low-density lipoprotein receptor adaptor protein (LDLrP).{{Cite web|url=http://blast.ncbi.nlm.nih.gov/Blast.cgi#alnHdr_37256045|title=FAM43A|website=NCBI protein BLAST|access-date=28 April 2018}}{{Cite web|url=http://genome.ucsd.edu|title=FAM43A|website=UCSC Genome Browser|access-date=28 April 2018}} Orthologs were identified in Mammalia, Aves, Actinopterygii, Reptilia, Hemichordata, Cephalochardata, Mollusca, Brachiopoda, Nematoda, and Arthropoda. No orthologs were identified beyond invertebrate species.{{Cite web|url=http://www.timetree.org|title=FAM43A protein|website=Timetree: The timescale of life|access-date=28 April 2018}} File:FAM43A unrooted phylogenic tree.png

FAM43A and paralog FAM43B comprise a specific gene family who share structural homology with the low-density lipoprotein receptor adaptor protein (LDLrP).{{Cite web|url=https://blast.ncbi.nlm.nih.gov/Blast.cgi#alnHdr_37256045|title=FAM43A|website=NCBI protein BLAST|access-date=28 April 2018}}

A distant homolog was identified using NCBI protein BLAST, low density lipoprotein receptor adaptor protein 1-like in [Cryptotermes secundus]. However, when the sequence LOC111863195 was compared to Homo sapiens, it was discovered that the homolog mapped to chromosome 1, making it an ortholog of the paralog FAM43B. The fact that FAM43A protein cannot be traced back any further in evolutionary history than invertebrates indicates that this could be the point that FAM43A and paralog FAM43B diverged, approximately 797 million years ago (MYA).

FAM43A protein is highly expressed in the mouth, vascular system, spleen and ear. Significant expression noted in the adipose tissue, umbilical cord, and bone, with highest expression in the infant developmental stage.{{Cite web|url=https://www.ncbi.nlm.nih.gov/unigene|title=FAM43A|website=NCBI UniGene|access-date=21 May 2018}}

Expression is upregulated in head and neck tumor and bladder carcinoma, suggesting an oncogenic function.{{Cite web|url=https://www.ncbi.nlm.nih.gov/UniGene|title=Homo sapiens FAM43A|website=NCBI UniGene|access-date=28 March 2018}} FAM43A expression is upregulated in Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) (GDS4299) and triple negative breast cancer (TNBC) cell lines Hs578T (GDS4092).{{Cite web|url=https://www.ncbi.nlm.nih.gov/geoprofiles/|title=GEO Profiles|website=NCBI GEO Profiles|access-date=5 May 2018}} FAM43A expression map of Mus musculus brain indicated differential expression in the cortex, corpus callosum, and hypothalamus.{{Cite web|url=http://mouse.brain-map.org/gene/show/86045|title=FAM43 expression|website=Allen Brain Atlas|access-date=31 March 2018}} The primary function of the corpus callosum is to innervate and connect the two hemispheres of the brain. The corpus callosum integrates motor, sensory, and cognitive performance between the cortical region in one hemisphere with its target in the other hemisphere.{{Cite web|url=http://cnsvp.stanford.edu/atlas/corpus_callosum.html|title=Corpus callosum|website=CNSvp|access-date=29 March 2018|archive-date=8 March 2018|archive-url=https://web.archive.org/web/20180308180213/http://cnsvp.stanford.edu/atlas/corpus_callosum.html|url-status=dead}} The hypothalamus links the nervous system to the endocrine system through the pituitary gland.

3q29 microdeletion syndrome (monosomy 3q29) is caused by interstitial deletions of 3q29, mediated by nonallelic homologous recombination between low-copy repeats resulting in a common deletion.{{Cite journal|vauthors=Ballif BC, etal |date=2008 |title=Expanding the clinical phenotype of the 3q29 microdeletion syndrome ad characterization of the reciprocal microduplication |journal=Molecular Cytogenetics |volume=1 |pages=8 |pmid=18471269 |pmc=2408925 |doi=10.1186/1755-8166-1-8 |doi-access=free }} 3q29 microdeletion syndrome is marked by the loss of 1.6 million base pairs, including 5 known genes and 17 unknown transcripts. Genes phosphate and cytidyltransferase 1, choline alpha (PYT1A), P21 (RAC1) activated kinase 2 (PAK2), melanotransferrin (MFI2), discs large MAGUK scaffold protein 1 (DLG1), and 3-hydroxybutyrate dehydrogenase 1 (BDH1) have been confirmed and another 7 genes have been implicated with incomplete cDNAs, and the remaining hypothetical genes are yet to be confirmed experimentally.{{Cite journal |vauthors=Willat L, etal |date=2005 |title=3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome |journal=American Journal of Human Genetics |volume=77 |issue=1 |pages=154–160 |pmid=15918153 |pmc=1226188 |doi=10.1086/431653}} Presentation of 3q29 microdeletion syndrome has shown increased risk for schizophrenia. Gene neighbors PAK2 and DLG1 have been implicated due to interaction with neuroligin and the AMPA receptor subunit GluR1.{{Cite journal |vauthors=Mulle JG, etal |date=2010 |title=Microdeletions of 3q29 confer high risk for Schizophrenia |journal=The American Journal of Human Genetics |volume=87 |issue=2 |pages=229–236 |pmid=20691406 |pmc=2917706 |doi=10.1016/j.ajhg.2010.07.013}} In 2015, Guida et al. identified a novel mutation proximal to the 3q29 microdeletion region that correlated with presentation of oculo auriculo vertebral spectrum (OAVS).{{cite journal|vauthors=Guida V, Sinibaldi L, Pagnoni M, Bernardini L, Loddo S, Margiotti K, Digilio MC, Fadda MT, Dallapiccola B, Iannetti G, Alessandro de L|date=April 2015|title=A de novo proximal 3q29 chromosome microduplication in a patient with oculo auriculo vertebral spectrum|journal=American Journal of Medical Genetics. Part A|volume=167A|issue=4|pages=797–801|doi=10.1002/ajmg.a.36951|pmid=25735547|s2cid=37704780}} Research of Robertson et al. revealed the presence of FAM43A mRNA in the fetal cochlea and association with development of normal hearing function.{{cite journal|vauthors=Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC|date=September 1994|title=Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening|journal=Genomics|volume=23|issue=1|pages=42–50|doi=10.1006/geno.1994.1457|pmid=7829101|hdl=10669/15162|hdl-access=free}} These findings indicate that variation in FAM43A could be responsible for the development of OAVS.

Transcription factor binding can be seen below within the FAM43A promoter region,{{Cite web|url=https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=a8ebc8d984a250774acaba31f79866a3|title=FAM43A|website=Genomatix|access-date=1 April 2018}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }} searches were completed on the 500 bp preceding the start codon.

MicroRNA binding sites were identified{{Cite web|url=http://www.targetscan.org/vert_72/|title=FAM43A microRNA binding sites|website=Targetscan|access-date=21 May 2018}} and then compared to species conservation of FAM43A to determine likely 3' untranslated region (UTR) stem loop structures as depicted to the right.

File:FAM43A 3'UTR.png

FAM43 is predicted to be a nuclear protein, to identify function, structure and function for LDL receptor adaptor protein (LDLrP) was completed.{{Cite web|url=https://psort.hgc.jp/form2.html|title=FAM43A|website=PSORT II Prediction|access-date=8 April 2018}} Conserved residues Y52 and S93 are highlighted in the structure of LDLrP to the right. Three phosphorylation sites were identified with conservation between human and mouse genotypes{{Cite web|url=https://www.phosphosite.org/homeAction.action|title=FAM43A phosphorylation sites|website=Phosphosite|access-date=8 April 2018}} at T112-p, S114-p, and T-379-p. The translated protein contains a primary and secondary nuclear localization signal and has a predicted GPI-linkage site at D407,{{Cite web|url=http://mendel.imp.ac.at/|title=FAM43A|website=IMP Bioinformatics|access-date=8 April 2018}} and a Caspase 3 and 7 cleavage site from amino acids 404-408{{Cite web|url=http://elm.eu.org|title=FAM43A motif search for nuclear protein|website=ELM|access-date=22 April 2018}} indicating possible translocation from the cell membrane to the nucleus. File:LDLrP phosphotyrosine domain.png

Direct interaction with SRPK2 (SRSF Protein Kinase 2), Serine/arginine-rich protein-specific kinase, which phosphorylates substrates at serine residues rich in Arginine/Serine dipeptides (RS domains), involved in the phosphorylation of SR splicing factors and the regulation of splicing. SRSF protein kinase 2 promotes neural apoptosis by up-regulating cyclin-D1 expression through the suppression of p53/TP53 phosphorylation.{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SRPK2|title=SRPK2 Gene|website=Gene Cards|access-date=1 May 2018}} Protein phosphatase 2A is one of the four major Ser/Thr phosphatases which regulate negative control of cell growth and division.{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5C|title=PPP2R5C|website=Gene Cards|access-date=1 May 2018}} FAM43A shows predicted interaction with the Abelson (ABL) kinase, and ABL members link diverse extracellular stimuli to signaling pathways controlling cell growth, survival, invasion, adhesion, and migration.{{Cite journal|last=Grueber|first=Emileigh K.|date=2013|title=Role of ABL Family Kinases in Cancer: from Leukemia to Solid Tumors|pmc=3935732|journal=Nature Reviews Cancer|volume=13 |issue=8|pages=559–571|doi=10.1038/nrc3563|pmid=23842646}}

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