FAM204A
| FAM204A | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | FAM204A, C10orf84, bA319I23.1, family with sequence similarity 204 member A | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | MGI: 1289174; HomoloGene: 41463; GeneCards: FAM204A; OMA:FAM204A - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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FAM204A (family with sequence similarity 204 member A) is a protein-coding gene that encodes the nuclear protein FAM204A in humans. The gene is located on chromosome 10 at position 10q26.11 and is ubiquitously expressed in human tissues.
Gene
FAM204A spans approximately 44 kilobases (kb) at chromosomal position 118.30 to 118.34 megabases (Mb) on the GRCh38 assembly and is transcribed from the minus (complementary) DNA strand.[5] It contains eight exons and produces two validated mRNA isoforms (NM_022063.3 and NM_001134672.2) that encode the same 233‑amino acid protein.[5] Other identifiers include C10orf84 and bA319I23.1.[5]
FAM204A's upstream neighbor is RAB11FIP2, which encodes a protein predicted to mediate protein kinase binding and dimerization and is expressed ubiquitously, with localization in the nucleoplasm and endosomal compartments.[6] Its downstream neighbor is the long non‐coding RNA CASC2 (cancer susceptibility candidate 2), implicated as a tumor suppressor and consistently observed to be downregulated in multiple cancer types.[7]
Protein
The human FAM204A protein is 233 amino acids in length with a molecular weight of approximately 27 kilodaltons (kDa) and a predicted isoelectric point (pI) near 7.7.[8]
FAM204A is lysine-rich and highly charged; nearly 40% of residues are basic or acidic. A lysine/arginine cluster between residues 95–114 resembles a nuclear localization signal (NLS) or nucleic acid-binding motif. No signal peptides or transmembrane regions are predicted, consistent with a soluble nuclear protein.
Subcellular localization
FAM204A is predicted to localize to the nucleus with high confidence by multiple computational tools. DeepLoc assigns a 0.90 probability for nuclear residency, while PSORT II identifies several monopartite and bipartite nuclear localization signals (e.g., KRRK at residue 100, bipartite motif KKHSEQKSTTSRFRGKR at residue 85).[9][10] SAPS compositional analysis highlights a positively charged segment (residues 95–114) typical of nuclear localization or nucleic acid-binding motifs.[8] Immunohistochemistry data show nuclear and nucleolar localization of FAM204A in human cells.[11]
Post-translational modifications
Predicted post-translational modifications include multiple phosphorylation sites (serine 17, serine 40, serine 93–105) and tyrosine phosphorylation (tyrosine 65, tyrosine 232), as well as motifs for SUMOylation and acetylation.[12][13] Experimental evidence supports phosphorylation at serine 152 (S152), ubiquitylation at lysine 128 (K128) and lysine 169 (K169), and acetylation at lysine 221 (K221) and lysine 222 (K222).[14]
Structure
AlphaFold predicts a largely disordered protein with a single α‑helical domain spanning residues 126–211 (CATH fold 1.10.287) and high model confidence (pLDDT ≈94).[15] This structured region may provide a stable core for interactions, while flanking regions remain intrinsically disordered.
Conservation
FAM204A is broadly conserved across opisthokonts, with orthologous proteins identified in mammals, birds, reptiles, amphibians, fish, basal chordates (e.g., lancelets and tunicates), basal metazoans (e.g., sponges and cnidarians), and fungi.[5] [16]
Vertebrate orthologs share higher sequence identity (~35–~90%) with human FAM204A, while more distant orthologs retain a more conserved C‑terminal region despite overall lower identity (~21-30).[17][18]
| Common name | Scientific Name | Divergence (MYA) | Accession # | Seq Length (AA) | Seq ID % | Seq Sim % |
|---|---|---|---|---|---|---|
| Human | Homo sapiens | 0 | NP_001128144.1 | 233 | 100.0 | 100.0 |
| Aye-aye | Daubentonia madagascariensis | 74 | KAL2769215.1 | 233 | 88.8 | 94.0 |
| Mouse | Mus musculus | 87 | NP_001345202.1 | 236 | 78.8 | 88.6 |
| Echidna | Tachyglossus aculeatus | 180 | XP_038614343.1 | 235 | 62.3 | 76.3 |
| Rhea | Rhea pennata | 319 | XP_062436011.1 | 244 | 55.7 | 71.5 |
| Chicken | Gallus gallus | 319 | XP_004942371.2 | 244 | 55.1 | 69.2 |
| Zebrafish | Danio rerio | 429 | NP_001002536.1 | 256 | 44.2 | 61.7 |
| Lamprey | Petromyzon marinus | 563 | XP_032817389.1 | 227 | 35.1 | 50.0 |
| Lancelet | Branchiostoma floridae | 581 | XP_035676714.1 | 212 | 28.6 | 42.7 |
| Sea squirt | Styela clava | 596 | XP_039271579.1 | 169 | 21.6 | 36.4 |
| Trichoplax | Trichoplax sp. H2 | 661 | RDD41954.1 | 227 | 21.7 | 40.4 |
| Manila clam | Ruditapes philippinarum | 686 | XP_060572578.1 | 202 | 30.5 | 42.9 |
| Deer tick | Ixodes scapularis | 686 | XP_002435965.3 | 220 | 27.1 | 45.0 |
| Ribbon worm | Lineus longissimus | 686 | XP_064649596.1 | 210 | 26.5 | 46.6 |
| Horseshoe crab | Limulus polyphemus | 686 | XP_013773511.1 | 288 | 26.3 | 42.8 |
| Sea anemone | Nematostella vectensis | 715 | EDO37736.1 | 216 | 25.2 | 39.1 |
| Sponge | Corticium candelabrum | 758 | XP_062502458.1 | 245 | 29.7 | 44.9 |
| Fungus | Rhizophagus clarus | 1275 | GES81201.1 | 206 | 27.4 | 42.9 |
| Anaerobic gut fungus | Anaeromyces robustus | 1275 | ORX87713.1 | 192 | 25.2 | 41.9 |
Expression
RNA-seq and microarray studies indicate that FAM204A is ubiquitously but variably expressed at moderately high levels across human tissues, with higher transcript levels in cerebellum, kidney, prostate, thymus, thyroid, adipose tissue, and testis.[5]
Interactions
High-throughput affinity capture–mass spectrometry (BioPlex) and yeast two-hybrid screens identify nuclear and chromatin-associated interactors of FAM204A. Reported partners include nuclear transport receptors (KPNA2, KPNA3, KPNB1), histone modifiers (H2AFJ, HAT1, KDM1A, SMYD1), and chaperones (HSP90AB1, DNAJC8).[19][20] These interactions suggest roles in nuclear import and chromatin regulation.
Clinical significance
No Mendelian disorders are currently attributed to FAM204A.[21] However, its locus on 10q26.11 has been implicated in complex traits. A genome‑wide linkage and association study identified this region as associated with late‑onset Alzheimer’s disease, although the signal may arise from FAM204A or neighboring genes within the locus.[22]
FAM204A is included in a U.S. patent (US 20140315736A1) disclosing blood‑based biomarker panels scored for Alzheimer's disease diagnosis, among which C10orf84/FAM204A is listed.[23] Variants in FAM204A also contribute to a polygenic "quit‑success" genotype score used to predict outcomes of smoking cessation therapy.[24]
Mouse knockout studies demonstrate that deletion of the Fam204a ortholog in mice results in pre‑weaning lethality, indicating that the gene may be essential for viability in mammals.[25]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000165669 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000057858 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e "FAM204A family with sequence similarity 204 member A [Homo sapiens (human)]". National Center for Biotechnology Information. Retrieved 29 July 2025.
- ^ "RAB11FIP2 RAB11 family interacting protein 2 [Homo sapiens (human)]". National Center for Biotechnology Information. Retrieved 6 July 2025.
- ^ "CASC2 cancer susceptibility 2 [Homo sapiens (human)]". National Center for Biotechnology Information. Retrieved 6 July 2025.
- ^ a b "SAPS (Statistical Analysis of Protein Sequences)". EMBL-EBI.
- ^ "DeepLoc: Subcellular Localization Prediction". DTU Health Tech.
- ^ "PSORT II: Protein Sorting Signal Prediction". NIG Japan.
- ^ "FAM204A protein expression summary". Human Protein Atlas.
- ^ "NetPhos 3.1 phosphorylation site prediction". DTU Health Tech.
- ^ "Eukaryotic Linear Motif (ELM) database". EMBL.
- ^ "PhosphoSitePlus FAM204A entry". Cell Signaling Technology.
- ^ "AlphaFold Protein Structure Database: FAM204A". EMBL-EBI.
- ^ "Basic Local Alignment Search Tool (BLAST)". National Center for Biotechnology Information. Retrieved 6 July 2025.
- ^ "Clustal Omega: Multiple Sequence Alignment". European Bioinformatics Institute (EMBL‑EBI). Retrieved 6 July 2025.
- ^ "EMBOSS Needle: Pairwise Sequence Alignment". European Bioinformatics Institute (EMBL‑EBI). Retrieved 6 July 2025.
- ^ BioPlex Protein–Protein Interaction Database [1]
- ^ BioGRID interaction database [2]
- ^ "Online Mendelian Inheritance in Man (OMIM)". Johns Hopkins University. Retrieved 6 July 2025.
- ^ Grupe, A. (2006). "A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease". American Journal of Human Genetics. 78 (1): 78–88. doi:10.1086/498851. PMC 1380225. PMID 16385451.
- ^ "Diagnostic biomarker profiles for the detection and diagnosis of Alzheimer's disease (US 20140315736A1)". United States Patent and Trademark Office. Retrieved 30 July 2025.
- ^ Rose, J. E. (2010). "Personalized smoking cessation: Interactions between nicotine dose, dependence, and quit-success genotype score". Molecular Medicine. 16 (7–8): 247–253. doi:10.2119/molmed.2009.00159. PMC 2896464. PMID 20379614.
- ^ "Mouse Genome Informatics: Fam204a phenotype". Jackson Laboratory.