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{{Infobox_gene}}
{{Infobox_gene}}


'''Protein FAM43A''' is a [[protein]] that is encoded in humans by the '''FAM43A [[gene]]'''. The acronym means "'''fam'''ily with sequence similarity '''43''', member '''A'''".<ref name="NCBI">[https://www.ncbi.nlm.nih.gov/gene/131583 NCBI entry on FAM43A]</ref> The specific function of FAM43A is currently unknown, and the gene has only been characterized in [[cDNA]] assays.<ref name="pmid15498874">{{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 = Proc Natl Acad Sci U S A | volume = 101 | issue = 44 | pages = 15724–15729 |date=Nov 2004 | pmid = 15498874 | pmc = 524842 | doi = 10.1073/pnas.0404089101}}</ref>
The family with sequence similarity 43 member A (FAM43A) gene, also known as; GCO3P195887, GC03P194406, GC03P191784,<ref>{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=FAM43A|title=FAM43A|last=|first=|date=|website=GeneCards|archive-url=|archive-date=|dead-url=|access-date=27 April 2018}}</ref> and NM_153690.3,<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/nuccore/NM_153690.4|title=FAM43A|last=|first=|date=|website=NCBI Nucleotide|archive-url=|archive-date=|dead-url=|access-date=27 April 2018}}</ref> codes for a 423 bp protein that is conserved in primates, and [[orthologs]] have been found in vertebrate and invertebrate species.<ref>{{cite web|title=Standard Protein Blast|url=https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE=Proteins|website=NCBI|publisher=National Library of Medicine|access-date=February 18, 2018}}</ref>  Three transcripts have been identified, two protein coding [[isoforms]] (aAug10, bAug10), and a non-coding transcript (cAug10).<ref>{{cite web|title=FAM43A gene|url=https://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/av.cgi?db=human&term=fam43a&submit=Go|website=NCBI AceView|access-date=February 4, 2018}}</ref> Molecular weight of 45.8 kdal in the unphosphorylated state and isoelectric point of 6.1.<ref>{{Cite web|url=https://www.edi.ac.uk|title=FAM43A|last=|first=|date=|website=SAPS|archive-url=|archive-date=|dead-url=|access-date=8 April 2018}}</ref>


==Characteristics==
==Gene==
FAM43A is located on [[chromosome 3]] at location 3q29.<ref name="NCBI"/> It encodes a 3182 base pair mRNA which possesses one [[Pleckstrin homology domain|Pleckstrin homology-like domain]]. The mRNA translates into LOC131583, a [[hydrophilic]] protein 423 [[amino acid]]s long.<ref name="NCBI"/><ref>[http://workbench.sdsc.edu/ SDSC Biology WorkBench]</ref> The protein has been predicted to localize in the [[Cell nucleus|nucleus]], and possesses  a cut signal [[peptide]] at amino acid 21.<ref>[http://ca.expasy.org/tools/ ExPASy Proteomics tools]</ref>
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.<ref>{{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}}</ref>


==Conservation==
==Introduction==
The FAM43A gene is [[Conserved sequence|conserved]] through a broad range of [[vertebrate]]s.<ref>[http://blast.ncbi.nlm.nih.gov/Blast.cgi NCBI blast]</ref> Conservation is extremely high among [[primates]], remaining significant among species as distant as [[zebrafish]].<ref>[http://ecrbrowser.dcode.org/xB.php?db=hg18&location=chr3:195887911-195891055 ECR browser]</ref>
The FAM43A gene has been identified in cDNA screening as a possible cancer development and progression candidate gene.<ref name="pmid15498874">{{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 }}</ref> Unpublished data from Zhang et al. indicates that FAM43A could possess tumor suppressor function<ref>{{cite web|title=FAM43A mRNA page|url=https://www.ncbi.nlm.nih.gov/nuccore/NM_153690.4|website=NCBI|access-date=February 4, 2018}}</ref> 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.<ref name="pmid24801482">{{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  }}</ref>  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.
 
==Protein==
FAM43A and paralog FAM43B comprise a specific gene family, and share structural homology with the low-density lipoprotein receptor adaptor protein (LDLrP).<ref>{{Cite web|url=http://blast.ncbi.nlm.nih.gov/Blast.cgi#alnHdr_37256045|title=FAM43A|last=|first=|date=|website=NCBI protein BLAST|archive-url=|archive-date=|dead-url=|access-date=28 April 2018}}</ref><ref>{{Cite web|url=http://genome.ucsd.edu|title=FAM43A|last=|first=|date=|website=UCSC Genome Browser|archive-url=|archive-date=|dead-url=|access-date=28 April 2018}}</ref>  Orthologs were identified in [[Mammalia]], [[Aves]], [[Actinopterygii]], [[Reptilia]], [[Hemichordata]], Cephalochardata, [[Mollusca]], [[Brachiopoda]], [[Nematoda]], and [[Arthropoda]].  No orthologs were identified beyond invertebrate species.<ref>{{Cite web|url=http://www.timetree.org|title=FAM43A protein|last=|first=|date=|website=Timetree: The timescale of life|archive-url=|archive-date=|dead-url=|access-date=28 April 2018}}</ref> [[File:FAM43A unrooted phylogenic tree.png|thumb|Unrooted Phylogenetic tree indicating orthologs in Mammalia, Aves, Actinoptergii, Reptilia, and several invertebrate species.]]
 
===Paralogs===
FAM43A and paralog FAM43B comprise a specific gene family who share structural homology with the low-density lipoprotein receptor adaptor protein (LDLrP).<ref>{{Cite web|url=https://blast.ncbi.nlm.nih.gov/Blast.cgi#alnHdr_37256045|title=FAM43A|last=|first=|date=|website=NCBI protein BLAST|archive-url=|archive-date=|dead-url=|access-date=28 April 2018}}</ref>
 
===Orthologs===
 
{| class="wikitable sortable"
|-
! Scientific Name !! Name !! Accession !! Sequence Similarity %
|-
| ''Gorilla gorilla'' || gorilla || [https://www.ncbi.nlm.nih.gov/protein/XP_004038285.1 XP_004038285.1] || 99
|-
| ''Orcinus orca'' || killer whale || [https://www.ncbi.nlm.nih.gov/protein/XP_004278817.1 XP_004278817.1] || 94
|-
| ''Gallus gallus'' || chicken || [https://www.ncbi.nlm.nih.gov/protein/XP_426700.2 XP_426700.2] || 74
|-
| ''Danio rerio'' || zebrafish || [https://www.ncbi.nlm.nih.gov/protein/NP_999870.1 NP_999870.1] || 71
|-
| ''Python bivittatus'' || python || [https://www.ncbi.nlm.nih.gov/protein/XP_007440325.1 XP_007440325.1] || 51
|-
| ''Branchiostoma belcheri'' || lancelet || [https://www.ncbi.nlm.nih.gov/protein/?term=XP_0196466582.1 XP_0196466582.1] || 49
|-
| ''Limulus polyphpemus'' || horseshoe crab || [https://www.ncbi.nlm.nih.gov/protein/XP_013779827.1 XP_013779827.1] || 38
|-
| ''Caenorhabditis elegans'' || nematode || [https://www.ncbi.nlm.nih.gov/protein/NP_509937.1 NP_509937.1] || 35
|}
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).
 
==Expression==
===Tissue specific expression===
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.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/unigene|title=FAM43A|last=|first=|date=|website=NCBI UniGene|archive-url=|archive-date=|dead-url=|access-date=21 May 2018}}</ref>
 
===Disease state expression===
Expression is upregulated in head and neck tumor and [[bladder carcinoma]], suggesting an oncogenic function.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/UniGene|title=Homo sapiens FAM43A|last=|first=|date=|website=NCBI UniGene|archive-url=|archive-date=|dead-url=|access-date=28 March 2018}}</ref>  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).<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/geoprofiles/|title=GEO Profiles|last=|first=|date=|website=NCBI GEO Profiles|archive-url=|archive-date=|dead-url=|access-date=5 May 2018}}</ref>  FAM43A expression map of ''Mus musculus''  brain indicated differential expression in the [[Cerebral cortex|cortex]], [[corpus callosum]], and [[hypothalamus]].<ref>{{Cite web|url=http://mouse.brain-map.org/gene/show/86045|title=FAM43 expression|last=|first=|date=|website=Allen Brain Atlas|archive-url=|archive-date=|dead-url=|access-date=31 March 2018}}</ref>  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.<ref>{{Cite web|url=http://cnsvp.stanford.edu/atlas/corpus_callosum.html|title=Corpus callosum|last=|first=|date=|website=CNSvp|archive-url=|archive-date=|dead-url=|access-date=29 March 2018}}</ref>  The hypothalamus links the nervous system to the endocrine system through the pituitary gland.
 
==Variation==
 
[[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.<ref>{{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}}</ref> 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.<ref>{{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}}</ref>  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.<ref>{{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}}</ref>  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).<ref name="pmid25735547">{{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}}</ref>  Research of Robertson et al. revealed the presence of FAM43A mRNA in the fetal cochlea and association with development of normal hearing function.<ref name="pmid7829101">{{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}}</ref>  These findings indicate that variation in FAM43A could be responsible for the development of OAVS.
 
===Promoter===
Transcription factor binding can be seen below within the FAM43A promoter region,<ref>{{Cite web|url=https://www.genomatix.de/cgi-bin/eldorado/eldorado.pl?s=a8ebc8d984a250774acaba31f79866a3|title=FAM43A|last=|first=|date=|website=Genomatix|archive-url=|archive-date=|dead-url=|access-date=1 April 2018}}</ref> searches were completed on the 500 bp preceding the start codon.
{| class="wikitable"
|+Candidate transcription factors and binding sites of ''FAM43A'' identified by Genomatix
|'''Matrix Family'''
!Detailed Family Information
!Anchor position
!Strand
!Matrix sim.
!Sequence
|-
|ZICF
|ZIC-family, zinc finger of the cerebellum
|1912
|<nowiki>-</nowiki>
|0.931
|{{DNA sequence|cggcgCAGCtgggcg}}
|-
|NEUR
|NeuroD, Beta2, HLH domain
|1912
|<nowiki>+</nowiki>
|0.985
|{{DNA sequence|cgcccaGCTGcgccg}}
|-
|PLAG
|Pleomorphic adenoma gene
|1919
|<nowiki>-</nowiki>
|0.931
|{{DNA sequence|ggaggGCGCcccggcgcagctgg}}
|-
|EGRF
|EGR/nerve growth factor induced protein C & related factors
|1896
|<nowiki>-</nowiki>
|0.919
|{{DNA sequence|ggcggcggCGGCggagcgc}}
|-
|KLFS
|kruppel like transcription factors
|1796
|<nowiki>-</nowiki>
|0.941
|{{DNA sequence|tagggagttGGGGggaggg}}
|-
|GCMF
|Chorion-specific transcription factors with a GCM DNA binding domain
|1742
|<nowiki>-</nowiki>
|0.919
|{{DNA sequence|attaCCCGcacctc}}
|-
|SORY
|SOX/SORY sex/testes determining and related HMG box factors
|1741
|<nowiki>+</nowiki>
|0.953
|{{DNA sequence|agagAATTtacccgcacctcctg}}
|-
|EBOX
|E-box binding factors
|1674
|<nowiki>+</nowiki>
|0.921
|{{DNA sequence|gtgcgcgCGTGtctccc}}
|-
|E2FF
|E2F-myc activator/cell cycle regulator
|1549
|<nowiki>+</nowiki>
|0.905
|{{DNA sequence|tgtgtGCGCgcgtgtct}}
|-
|MTF1
|Metal induced transcription factor
|1635
|<nowiki>+</nowiki>
|0.900
|{{DNA sequence|ctttGCTCtcgccct}}
|-
|ETSF
|Human and murine ETS1 factors
|1565
|<nowiki>-</nowiki>
|0.934
|{{DNA sequence|aaatgtcaGGAAaaaagctag}}
|-
|FKHD
|Forkhead domain factors
|1541
|<nowiki>-</nowiki>
|0.986
|{{DNA sequence|cgcgtgcAAATaaagag}}
|-
|INSN
|Insulinoma associated factors
|1462
|<nowiki>+</nowiki>
|0.926
|{{DNA sequence|tgttaGGGGaccc}}
|}
 
===3' untranslated region===
MicroRNA binding sites were identified<ref>{{Cite web|url=http://www.targetscan.org/vert_72/|title=FAM43A microRNA binding sites|last=|first=|date=|website=Targetscan|archive-url=|archive-date=|dead-url=|access-date=21 May 2018}}</ref> 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|thumb|3' untranslated region secondary structure]]
 
===Post-translational Modification===
 
FAM43 is predicted to be a [[nuclear protein]], to identify function, structure and function for LDL receptor adaptor protein (LDLrP) was completed.<ref>{{Cite web|url=https://psort.hgc.jp/form2.html|title=FAM43A|last=|first=|date=|website=PSORT II Prediction|archive-url=|archive-date=|dead-url=|access-date=8 April 2018}}</ref>  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<ref>{{Cite web|url=https://www.phosphosite.org/homeAction.action|title=FAM43A phosphorylation sites|last=|first=|date=|website=Phosphosite|archive-url=|archive-date=|dead-url=|access-date=8 April 2018}}</ref> 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,<ref>{{Cite web|url=http://mendel.imp.ac.at/|title=FAM43A|last=|first=|date=|website=IMP Bioinformatics|archive-url=|archive-date=|dead-url=|access-date=8 April 2018}}</ref> and a Caspase 3 and 7 cleavage site from amino acids 404-408<ref>{{Cite web|url=http://elm.eu.org|title=FAM43A motif search for nuclear protein|last=|first=|date=|website=ELM|archive-url=|archive-date=|dead-url=|access-date=22 April 2018}}</ref> indicating possible translocation from the [[cell membrane]] to the [[Cell nucleus|nucleus]]. [[File:LDLrP phosphotyrosine domain.png|thumb|LDLrP phosphotyrosine interaction domain with Y52 and S93 highlighted.]]
 
==Interacting Proteins==
 
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.<ref>{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SRPK2|title=SRPK2 Gene|last=|first=|date=|website=Gene Cards|archive-url=|archive-date=|dead-url=|access-date=1 May 2018}}</ref>  Protein phosphatase 2A is one of the four major Ser/Thr phosphatases which regulate negative control of cell growth and division.<ref>{{Cite web|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPP2R5C|title=PPP2R5C|last=|first=|date=|website=Gene Cards|archive-url=|archive-date=|dead-url=|access-date=1 May 2018}}</ref>  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.<ref>{{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}}</ref>
 
{| class="wikitable sortable"
|-
! Interacting protein alias !! Full name !! Function !! Interaction Type
|-
| SRPK2 || Serine/arginine-rich protein-specific kinase || Phosphorylates substrates at RS domains || direct interaction
|-
| PPP2R5C || Protein Phosphatase 2A Regulatory Subunit B'Gamma || Phosphatase 2A regulatory subunit B family || physical association
|-
| PPP2R1B || Protein Phosphatase 2A Scaffold Subunit A beta || constant regulatory subunit of protein phosphatase 2 || physical association
|-
| PPP2R5D || Protein Phosphatase 2A Regulatory Subunit B'Delta || Phosphatase 2A regulatory subunit B family || physical association
|-
| PPP2R5A || Protein Phosphatase 2A Regulatory Subunit B'Alpha || Phosphatase 2A regulatory subunit B family|| physical association
|-
| PPP2R5B || Protein Phosphatase 2A Regulatory Subunit B'Beta|| Phosphatase 2A regulatory subunit B family || physical association
|-
| PPP2R5E || Protein Phosphatase 2A Regulatory Subunit B'Epsilon || Phosphastase 2A regulatory subunit B family || physical association
|-
| SNX6 || Sorting Nexin 6 || Members contain a phox (PX) phosphoinositide binding domain (intracellular trafficking) || physical association
|}


==References==
==References==
{{reflist}}
{{reflist}}
{{PDB Gallery|geneid=131583}}

Latest revision as of 23:15, 30 August 2018

VALUE_ERROR (nil)
Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

The family with sequence similarity 43 member A (FAM43A) gene, also known as; GCO3P195887, GC03P194406, GC03P191784,[1] and NM_153690.3,[2] codes for a 423 bp protein that is conserved in primates, and orthologs have been found in vertebrate and invertebrate species.[3] Three transcripts have been identified, two protein coding isoforms (aAug10, bAug10), and a non-coding transcript (cAug10).[4] Molecular weight of 45.8 kdal in the unphosphorylated state and isoelectric point of 6.1.[5]

Gene

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.[6]

Introduction

The FAM43A gene has been identified in cDNA screening as a possible cancer development and progression candidate gene.[7] Unpublished data from Zhang et al. indicates that FAM43A could possess tumor suppressor function[8] 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.[9] 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.

Protein

FAM43A and paralog FAM43B comprise a specific gene family, and share structural homology with the low-density lipoprotein receptor adaptor protein (LDLrP).[10][11] Orthologs were identified in Mammalia, Aves, Actinopterygii, Reptilia, Hemichordata, Cephalochardata, Mollusca, Brachiopoda, Nematoda, and Arthropoda. No orthologs were identified beyond invertebrate species.[12]

File:FAM43A unrooted phylogenic tree.png
Unrooted Phylogenetic tree indicating orthologs in Mammalia, Aves, Actinoptergii, Reptilia, and several invertebrate species.

Paralogs

FAM43A and paralog FAM43B comprise a specific gene family who share structural homology with the low-density lipoprotein receptor adaptor protein (LDLrP).[13]

Orthologs

Scientific Name Name Accession Sequence Similarity %
Gorilla gorilla gorilla XP_004038285.1 99
Orcinus orca killer whale XP_004278817.1 94
Gallus gallus chicken XP_426700.2 74
Danio rerio zebrafish NP_999870.1 71
Python bivittatus python XP_007440325.1 51
Branchiostoma belcheri lancelet XP_0196466582.1 49
Limulus polyphpemus horseshoe crab XP_013779827.1 38
Caenorhabditis elegans nematode NP_509937.1 35

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).

Expression

Tissue specific expression

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.[14]

Disease state expression

Expression is upregulated in head and neck tumor and bladder carcinoma, suggesting an oncogenic function.[15] 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).[16] FAM43A expression map of Mus musculus brain indicated differential expression in the cortex, corpus callosum, and hypothalamus.[17] 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.[18] The hypothalamus links the nervous system to the endocrine system through the pituitary gland.

Variation

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.[19] 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.[20] 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.[21] 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).[22] Research of Robertson et al. revealed the presence of FAM43A mRNA in the fetal cochlea and association with development of normal hearing function.[23] These findings indicate that variation in FAM43A could be responsible for the development of OAVS.

Promoter

Transcription factor binding can be seen below within the FAM43A promoter region,[24] searches were completed on the 500 bp preceding the start codon.

Candidate transcription factors and binding sites of FAM43A identified by Genomatix
Matrix Family Detailed Family Information Anchor position Strand Matrix sim. Sequence
ZICF ZIC-family, zinc finger of the cerebellum 1912 - 0.931 cggcgCAGCtgggcg
NEUR NeuroD, Beta2, HLH domain 1912 + 0.985 cgcccaGCTGcgccg
PLAG Pleomorphic adenoma gene 1919 - 0.931 ggaggGCGCcccggcgcagctgg
EGRF EGR/nerve growth factor induced protein C & related factors 1896 - 0.919 ggcggcggCGGCggagcgc
KLFS kruppel like transcription factors 1796 - 0.941 tagggagttGGGGggaggg
GCMF Chorion-specific transcription factors with a GCM DNA binding domain 1742 - 0.919 attaCCCGcacctc
SORY SOX/SORY sex/testes determining and related HMG box factors 1741 + 0.953 agagAATTtacccgcacctcctg
EBOX E-box binding factors 1674 + 0.921 gtgcgcgCGTGtctccc
E2FF E2F-myc activator/cell cycle regulator 1549 + 0.905 tgtgtGCGCgcgtgtct
MTF1 Metal induced transcription factor 1635 + 0.900 ctttGCTCtcgccct
ETSF Human and murine ETS1 factors 1565 - 0.934 aaatgtcaGGAAaaaagctag
FKHD Forkhead domain factors 1541 - 0.986 cgcgtgcAAATaaagag
INSN Insulinoma associated factors 1462 + 0.926 tgttaGGGGaccc

3' untranslated region

MicroRNA binding sites were identified[25] 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
3' untranslated region secondary structure

Post-translational Modification

FAM43 is predicted to be a nuclear protein, to identify function, structure and function for LDL receptor adaptor protein (LDLrP) was completed.[26] 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[27] 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,[28] and a Caspase 3 and 7 cleavage site from amino acids 404-408[29] indicating possible translocation from the cell membrane to the nucleus.

File:LDLrP phosphotyrosine domain.png
LDLrP phosphotyrosine interaction domain with Y52 and S93 highlighted.

Interacting Proteins

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.[30] Protein phosphatase 2A is one of the four major Ser/Thr phosphatases which regulate negative control of cell growth and division.[31] 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.[32]

Interacting protein alias Full name Function Interaction Type
SRPK2 Serine/arginine-rich protein-specific kinase Phosphorylates substrates at RS domains direct interaction
PPP2R5C Protein Phosphatase 2A Regulatory Subunit B'Gamma Phosphatase 2A regulatory subunit B family physical association
PPP2R1B Protein Phosphatase 2A Scaffold Subunit A beta constant regulatory subunit of protein phosphatase 2 physical association
PPP2R5D Protein Phosphatase 2A Regulatory Subunit B'Delta Phosphatase 2A regulatory subunit B family physical association
PPP2R5A Protein Phosphatase 2A Regulatory Subunit B'Alpha Phosphatase 2A regulatory subunit B family physical association
PPP2R5B Protein Phosphatase 2A Regulatory Subunit B'Beta Phosphatase 2A regulatory subunit B family physical association
PPP2R5E Protein Phosphatase 2A Regulatory Subunit B'Epsilon Phosphastase 2A regulatory subunit B family physical association
SNX6 Sorting Nexin 6 Members contain a phox (PX) phosphoinositide binding domain (intracellular trafficking) physical association

References

  1. ↑ "FAM43A". GeneCards. Retrieved 27 April 2018.
  2. ↑ "FAM43A". NCBI Nucleotide. Retrieved 27 April 2018.
  3. ↑ "Standard Protein Blast". NCBI. National Library of Medicine. Retrieved February 18, 2018.
  4. ↑ "FAM43A gene". NCBI AceView. Retrieved February 4, 2018.
  5. ↑ "FAM43A". SAPS. Retrieved 8 April 2018.
  6. ↑ "NCBI Protein". NCBI. U.S. National Library of Medicine. Retrieved February 18, 2018.
  7. ↑ 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 (November 2004). "Large-scale cDNA transfection screening for genes related to cancer development and progression". Proceedings of the National Academy of Sciences of the United States of America. 101 (44): 15724–9. doi:10.1073/pnas.0404089101. PMC 524842. PMID 15498874.
  8. ↑ "FAM43A mRNA page". NCBI. Retrieved February 4, 2018.
  9. ↑ 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 (2014). "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". PLOS One. 9 (5): e96374. doi:10.1371/journal.pone.0096374. PMC 4011843. PMID 24801482.
  10. ↑ "FAM43A". NCBI protein BLAST. Retrieved 28 April 2018.
  11. ↑ "FAM43A". UCSC Genome Browser. Retrieved 28 April 2018.
  12. ↑ "FAM43A protein". Timetree: The timescale of life. Retrieved 28 April 2018.
  13. ↑ "FAM43A". NCBI protein BLAST. Retrieved 28 April 2018.
  14. ↑ "FAM43A". NCBI UniGene. Retrieved 21 May 2018.
  15. ↑ "Homo sapiens FAM43A". NCBI UniGene. Retrieved 28 March 2018.
  16. ↑ "GEO Profiles". NCBI GEO Profiles. Retrieved 5 May 2018.
  17. ↑ "FAM43 expression". Allen Brain Atlas. Retrieved 31 March 2018.
  18. ↑ "Corpus callosum". CNSvp. Retrieved 29 March 2018.
  19. ↑ Ballif BC, et al. (2008). "Expanding the clinical phenotype of the 3q29 microdeletion syndrome ad characterization of the reciprocal microduplication". Molecular Cytogenetics. 1: 8. doi:10.1186/1755-8166-1-8. PMC 2408925. PMID 18471269.
  20. ↑ Willat L, et al. (2005). "3q29 Microdeletion Syndrome: Clinical and Molecular Characterization of a New Syndrome". American Journal of Human Genetics. 77 (1): 154–160. doi:10.1086/431653. PMC 1226188. PMID 15918153.
  21. ↑ Mulle JG, et al. (2010). "Microdeletions of 3q29 confer high risk for Schizophrenia". The American Journal of Human Genetics. 87 (2): 229–236. doi:10.1016/j.ajhg.2010.07.013. PMC 2917706. PMID 20691406.
  22. ↑ Guida V, Sinibaldi L, Pagnoni M, Bernardini L, Loddo S, Margiotti K, Digilio MC, Fadda MT, Dallapiccola B, Iannetti G, Alessandro de L (April 2015). "A de novo proximal 3q29 chromosome microduplication in a patient with oculo auriculo vertebral spectrum". American Journal of Medical Genetics. Part A. 167A (4): 797–801. doi:10.1002/ajmg.a.36951. PMID 25735547.
  23. ↑ Robertson NG, Khetarpal U, Gutiérrez-Espeleta GA, Bieber FR, Morton CC (September 1994). "Isolation of novel and known genes from a human fetal cochlear cDNA library using subtractive hybridization and differential screening". Genomics. 23 (1): 42–50. doi:10.1006/geno.1994.1457. PMID 7829101.
  24. ↑ "FAM43A". Genomatix. Retrieved 1 April 2018.
  25. ↑ "FAM43A microRNA binding sites". Targetscan. Retrieved 21 May 2018.
  26. ↑ "FAM43A". PSORT II Prediction. Retrieved 8 April 2018.
  27. ↑ "FAM43A phosphorylation sites". Phosphosite. Retrieved 8 April 2018.
  28. ↑ "FAM43A". IMP Bioinformatics. Retrieved 8 April 2018.
  29. ↑ "FAM43A motif search for nuclear protein". ELM. Retrieved 22 April 2018.
  30. ↑ "SRPK2 Gene". Gene Cards. Retrieved 1 May 2018.
  31. ↑ "PPP2R5C". Gene Cards. Retrieved 1 May 2018.
  32. ↑ Grueber, Emileigh K. (2013). "Role of ABL Family Kinases in Cancer: from Leukemia to Solid Tumors". Nature Reviews Cancer. 13 (8): 559–571. doi:10.1038/nrc3563. PMC 3935732.
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