FAM43A

Last updated
FAM43A
Identifiers
Aliases FAM43A , family with sequence similarity 43 member A
External IDs MGI: 2676309 HomoloGene: 17800 GeneCards: FAM43A
Orthologs
SpeciesHumanMouse
Entrez

131583

224093

Ensembl

ENSG00000185112

ENSMUSG00000046546

UniProt

Q8N2R8

Q8BUP8

RefSeq (mRNA)

NM_153690

NM_177632

RefSeq (protein)

NP_710157

NP_808300

Location (UCSC) Chr 3: 194.69 – 194.69 Mb Chr 16: 30.42 – 30.42 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The family with sequence similarity 43 member A (FAM43A) gene, also known as; GCO3P195887, GC03P194406, GC03P191784, [5] and NM_153690.3, [6] codes for a 423 bp protein that is conserved in primates, and orthologs have been found in vertebrate and invertebrate species. [7] Three transcripts have been identified, two protein coding isoforms (aAug10, bAug10), and a non-coding transcript (cAug10). [8] Molecular weight of 45.8 kdal in the unphosphorylated state and isoelectric point of 6.1. [9]

Contents

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. [10]

Introduction

The FAM43A gene has been identified in cDNA screening as a possible cancer development and progression candidate gene. [11] Unpublished data from Zhang et al. indicates that FAM43A could possess tumor suppressor function [12] 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. [13] 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). [14] [15] Orthologs were identified in Mammalia, Aves, Actinopterygii, Reptilia, Hemichordata, Cephalochardata, Mollusca, Brachiopoda, Nematoda, and Arthropoda. No orthologs were identified beyond invertebrate species. [16]

Unrooted Phylogenetic tree indicating orthologs in Mammalia, Aves, Actinoptergii, Reptilia, and several invertebrate species. 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). [17]

Orthologs

Scientific NameNameAccessionSequence Similarity %
Gorilla gorillagorilla XP_004038285.1 99
Orcinus orcakiller whale XP_004278817.1 94
Gallus galluschicken XP_426700.2 74
Danio reriozebrafish NP_999870.1 71
Python bivittatuspython XP_007440325.1 51
Branchiostoma belcherilancelet XP_0196466582.1 49
Limulus polyphpemushorseshoe crab XP_013779827.1 38
Caenorhabditis elegansnematode 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. [18]

Disease state expression

Expression is upregulated in head and neck tumor and bladder carcinoma, suggesting an oncogenic function. [19] 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). [20] FAM43A expression map of Mus musculus brain indicated differential expression in the cortex, corpus callosum, and hypothalamus. [21] 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. [22] 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. [23] 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. [24] 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. [25] 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). [26] Research of Robertson et al. revealed the presence of FAM43A mRNA in the fetal cochlea and association with development of normal hearing function. [27] 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, [28] searches were completed on the 500 bp preceding the start codon.

Candidate transcription factors and binding sites of FAM43A identified by Genomatix
Matrix FamilyDetailed Family InformationAnchor positionStrandMatrix sim.Sequence
ZICFZIC-family, zinc finger of the cerebellum1912-0.931cggcgCAGCtgggcg
NEURNeuroD, Beta2, HLH domain1912+0.985cgcccaGCTGcgccg
PLAGPleomorphic adenoma gene1919-0.931ggaggGCGCcccggcgcagctgg
EGRFEGR/nerve growth factor induced protein C & related factors1896-0.919ggcggcggCGGCggagcgc
KLFSkruppel like transcription factors1796-0.941tagggagttGGGGggaggg
GCMFChorion-specific transcription factors with a GCM DNA binding domain1742-0.919attaCCCGcacctc
SORYSOX/SORY sex/testes determining and related HMG box factors1741+0.953agagAATTtacccgcacctcctg
EBOXE-box binding factors1674+0.921gtgcgcgCGTGtctccc
E2FFE2F-myc activator/cell cycle regulator1549+0.905tgtgtGCGCgcgtgtct
MTF1Metal induced transcription factor1635+0.900ctttGCTCtcgccct
ETSFHuman and murine ETS1 factors1565-0.934aaatgtcaGGAAaaaagctag
FKHDForkhead domain factors1541-0.986cgcgtgcAAATaaagag
INSNInsulinoma associated factors1462+0.926tgttaGGGGaccc

3' untranslated region

MicroRNA binding sites were identified [29] and then compared to species conservation of FAM43A to determine likely 3' untranslated region (UTR) stem loop structures as depicted to the right.

3' untranslated region secondary structure 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. [30] 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 [31] 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, [32] and a Caspase 3 and 7 cleavage site from amino acids 404-408 [33] indicating possible translocation from the cell membrane to the nucleus.

LDLrP phosphotyrosine interaction domain with Y52 and S93 highlighted. 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. [34] Protein phosphatase 2A is one of the four major Ser/Thr phosphatases which regulate negative control of cell growth and division. [35] 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. [36]

Interacting protein aliasFull nameFunctionInteraction Type
SRPK2Serine/arginine-rich protein-specific kinasePhosphorylates substrates at RS domainsdirect interaction
PPP2R5CProtein Phosphatase 2A Regulatory Subunit B'GammaPhosphatase 2A regulatory subunit B familyphysical association
PPP2R1BProtein Phosphatase 2A Scaffold Subunit A betaconstant regulatory subunit of protein phosphatase 2physical association
PPP2R5DProtein Phosphatase 2A Regulatory Subunit B'DeltaPhosphatase 2A regulatory subunit B familyphysical association
PPP2R5AProtein Phosphatase 2A Regulatory Subunit B'AlphaPhosphatase 2A regulatory subunit B familyphysical association
PPP2R5BProtein Phosphatase 2A Regulatory Subunit B'BetaPhosphatase 2A regulatory subunit B familyphysical association
PPP2R5EProtein Phosphatase 2A Regulatory Subunit B'EpsilonPhosphastase 2A regulatory subunit B familyphysical association
SNX6Sorting Nexin 6Members contain a phox (PX) phosphoinositide binding domain (intracellular trafficking)physical association

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<span class="mw-page-title-main">FAM98C</span> Gene

Family with sequence 98, member C or FAM98C is a gene that encodes for FAM98C has two aliases FLJ44669 and hypothetical protein LOC147965. FAM98C has two paralogs in humans FAM98A and FAM98B. FAM98C can be characterized for being a Leucine-rich protein. The function of FAM98C is still not defined. FAM98C has orthologs in mammals, reptiles, and amphibians and has a distant orhtologs in Rhinatrema bivittatum and Nanorana parkeri.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000185112 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000046546 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "FAM43A". GeneCards. Retrieved 27 April 2018.
  6. ↑ "FAM43A". NCBI Nucleotide. Retrieved 27 April 2018.
  7. ↑ "Standard Protein Blast". NCBI. National Library of Medicine. Retrieved February 18, 2018.
  8. ↑ "FAM43A gene". NCBI AceView. Retrieved February 4, 2018.
  9. ↑ "FAM43A". SAPS. Retrieved 8 April 2018.[ permanent dead link ]
  10. ↑ "NCBI Protein". NCBI. U.S. National Library of Medicine. Retrieved February 18, 2018.
  11. ↑ 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. Bibcode:2004PNAS..10115724W. doi: 10.1073/pnas.0404089101 . PMC   524842 . PMID   15498874.
  12. ↑ "FAM43A mRNA page". NCBI. Retrieved February 4, 2018.
  13. ↑ 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. Bibcode:2014PLoSO...996374B. doi: 10.1371/journal.pone.0096374 . PMC   4011843 . PMID   24801482.
  14. ↑ "FAM43A". NCBI protein BLAST. Retrieved 28 April 2018.
  15. ↑ "FAM43A". UCSC Genome Browser. Retrieved 28 April 2018.
  16. ↑ "FAM43A protein". Timetree: The timescale of life. Retrieved 28 April 2018.
  17. ↑ "FAM43A". NCBI protein BLAST. Retrieved 28 April 2018.
  18. ↑ "FAM43A". NCBI UniGene. Retrieved 21 May 2018.
  19. ↑ "Homo sapiens FAM43A". NCBI UniGene. Retrieved 28 March 2018.
  20. ↑ "GEO Profiles". NCBI GEO Profiles. Retrieved 5 May 2018.
  21. ↑ "FAM43 expression". Allen Brain Atlas. Retrieved 31 March 2018.
  22. ↑ "Corpus callosum". CNSvp. Archived from the original on 8 March 2018. Retrieved 29 March 2018.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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. S2CID   37704780.
  27. ↑ 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.
  28. ↑ "FAM43A". Genomatix. Retrieved 1 April 2018.
  29. ↑ "FAM43A microRNA binding sites". Targetscan. Retrieved 21 May 2018.
  30. ↑ "FAM43A". PSORT II Prediction. Retrieved 8 April 2018.
  31. ↑ "FAM43A phosphorylation sites". Phosphosite. Retrieved 8 April 2018.
  32. ↑ "FAM43A". IMP Bioinformatics. Retrieved 8 April 2018.
  33. ↑ "FAM43A motif search for nuclear protein". ELM. Retrieved 22 April 2018.
  34. ↑ "SRPK2 Gene". Gene Cards. Retrieved 1 May 2018.
  35. ↑ "PPP2R5C". Gene Cards. Retrieved 1 May 2018.
  36. ↑ 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 . PMID   23842646.
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