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]
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FAM43A gene has been identified in cDNA screening as a possible cancer development and progression candidate gene.[7] Unpublished data from Zhang et al.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.
File:FAM43A unrooted phylogenic tree.pngUnrooted 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]
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 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.
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.
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)
↑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. PMID25735547.
↑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. PMID7829101.
