AARD

UniProt ID: Q4LEZ3
Organism: Homo sapiens
Review Status: COMPLETE
πŸ“ Provide Detailed Feedback

Gene Description

AARD (alanine- and arginine-rich domain-containing protein, C8orf85) is an uncharacterised small protein. No molecular activity, subcellular location or cellular function has been established for it: UniProt records no FUNCTION and no SUBCELLULAR LOCATION, and the only experimental information in GO consists of binding partners from a single high-throughput yeast two-hybrid screen. What is known comes from mouse expression studies. Aard transcription is essentially restricted to Sertoli cells of the testis, rising during testis differentiation in step with the formation of testis cords and increasing further with age, and it is a direct transcriptional target of the androgen receptor - AARD protein is significantly downregulated in Sertoli-cell-selective androgen receptor knockout mice. AARD is therefore best described at present as an androgen-responsive, Sertoli-cell- specific gene product of unknown biochemical function; whether it acts in spermatogenesis itself, rather than merely being expressed there, has not been tested.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome.
MARK AS OVER ANNOTATED
Summary: This single entry stands for all 15 rows in the GOA file: they carry an identical term, qualifier, evidence code and reference, and differ only in the WITH/FROM partner, so they are one annotation supported by 15 interactors, all from the HuRI binary interactome. It is also the entirety of AARD's GO record - the gene has no molecular function beyond binding, no cellular component and no biological process. Rather than discount the set on the usual grounds (single publication, no follow-up), a specific alternative explanation was tested against a null model: coiled-coil bias, the known tendency of sticky or self-activating yeast two-hybrid preys to recover coiled-coil proteins through promiscuous heptad-repeat association. Seven of the fifteen partners carry a coiled-coil FEATURE. Against a background of 2059 of 20431 reviewed human proteins with that same feature (10.1%), fetched from UniProt for this purpose, that is a 4.6-fold enrichment with a binomial P(X>=7 | n=15, p=0.101) of 3.3e-04. Numerator and denominator use the same criterion deliberately: two further partners (KRT24, KRT27) carry only the Coiled coil KEYWORD, which UniProt assigns more liberally than the feature, and scoring them in against a feature-only background would overstate the enrichment. On the consistent feature-or-keyword pair it is 9 of 15 against a 10.6% keyword background, 5.6-fold, P = 4.8e-06 - the same conclusion either way. With n=15 this remains a descriptive statistic rather than a controlled test. The partners also come from irreconcilable compartments. Collapsing UniProt's hierarchical location strings to their leading term gives 14 top-level compartments across 15 proteins. Three partners are syntaxins (STX1A, STX2, STX5) - SNAREs from three different membranes that share a coiled-coil SNARE motif - and two are keratins (KRT24, KRT27). The remainder include centrosomal and centromeric coiled-coil proteins (CEP57, KIAA0753, CENPQ), a nuclear splicing factor (TFIP11), an endosomal protein (VPS37C), a secreted protein and a transcription factor (LMO4). There is no compartment in which these could plausibly meet, and what they share is architecture rather than biology. Marked over-annotated rather than removed: the interactions may genuinely have occurred in the assay, and there is no positive evidence that any individual pair is false. But the set as a whole should not be read as AARD's interactome, and bare protein binding conveys nothing about its function in any case.
Reason: A single high-throughput screen contributing every annotation the gene has, with a partner set that matches the coiled-coil Y2H artefact signature (7/15 with a coiled-coil feature, a 4.6-fold enrichment over the 10.1% human background; 14 top-level compartments; three syntaxins and two keratins) and no functional follow-up for any pair, recorded under an uninformative term.
Supporting Evidence:
file:human/AARD/AARD-bioinformatics/RESULTS.md
If the partners come from unrelated compartments but share coiled-coil architecture, the assay explains the set better than any function does.
file:human/AARD/AARD-deep-research-affinage.md
no molecular activity, interaction partners, or cellular function for AARD have been characterized in the available corpus

References

Loading supporting content…

Download this section (compressed HTML)

Suggested Questions for Experts

Q: Does AARD have any molecular function at all? This is the primary gap and nothing currently constrains the answer: no catalytic motif, no subcellular location, and an interactome that appears to be an assay artefact. Even the affinage mechanism profile reports no molecular activity, no localisation and no partners. AARD does have a family - PANTHER PTHR32289, InterPro IPR051771, the FAM167 family shared with FAM167A and FAM167B - but that route is closed too: all 10 reviewed members of the family lack a UniProt FUNCTION statement, and UniProt's PAN-GO line for AARD records "0 GO annotations based on evolutionary models".

Q: Is AARD functionally required in Sertoli cells, or only expressed there? Everything known about this gene is expression biology - Sertoli-cell-restricted transcription that rises during testis differentiation and is directly driven by the androgen receptor. No loss-of-function experiment has been reported, so whether AARD does anything in spermatogenesis is untested.

Q: Should any of the 15 reported interactions be believed individually? The coiled-coil analysis argues against the set as a whole, but it cannot exclude a genuine interaction hiding inside it. Retesting the least artefact-prone partners - the six without coiled-coil regions - by co-immunoprecipitation at endogenous levels would separate the two possibilities.

Q: Can the FAM167 family be cracked as a unit? AARD, FAM167A and FAM167B share a family with no described function in any of its 10 reviewed members across 5 species. That is unusual for a conserved vertebrate family and suggests a coordinated effort - solving any one member would likely illuminate the others, and the family's uniform darkness means no member is currently a better starting point than another.

Q: Where does AARD protein localise? A single reliable subcellular localisation would immediately narrow the space of possible functions and would provide the first independent test of the interactome, since a genuine partner has to share a compartment.

Suggested Experiments

Experiment: Re-test the 15 reported partners by co-immunoprecipitation of endogenously tagged AARD in a cell type that expresses it, and in parallel check whether AARD scores as a frequent prey across unrelated baits in the source dataset. A high recovery rate would rescue the annotations; near-zero recovery, combined with the coiled-coil bias already shown, would justify removing them outright rather than flagging them.

Hypothesis: AARD's reported interactome is an artefact of coiled-coil promiscuity in yeast two-hybrid rather than a partner set.

Type: interaction validation

Experiment: Generate a Sertoli-cell-specific Aard knockout mouse and assess testis cord formation, Sertoli cell maturation, spermatogenesis and fertility. Since the gene is an androgen receptor target, compare the phenotype with the Sertoli-cell-selective AR knockout to establish whether AARD mediates any part of the AR programme.

Hypothesis: AARD is functionally required in Sertoli cells, not merely expressed there.

Type: mouse genetics

Experiment: Localise endogenously tagged AARD by imaging and by fractionation in a Sertoli cell model, and in parallel assess whether the protein is intrinsically disordered or adopts a fold, by circular dichroism and NMR on recombinant protein together with structure prediction. An intrinsically disordered result would itself be informative and would reframe the interactome question.

Hypothesis: AARD has a determinable subcellular localisation and a structured core despite its compositional-bias name.

Type: cell biology and biophysics

Experiment: Mine single-cell and bulk testis transcriptomic datasets for genes tightly co-expressed with AARD across developmental stages and across species, and test whether the resulting module points to a coherent process. For a gene whose only reliable data is expression, guilt-by-association across conditions is a better lead than its interactome.

Hypothesis: AARD's function can be inferred from co-expression rather than from interaction data.

Type: computational transcriptomics

Deep Research

Affinage

(AARD-deep-research-affinage.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“š Additional Documentation

Notes

(AARD-notes.md)

Loading supporting content…

Download this section (compressed HTML)

Bioinformatics Results

(RESULTS.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“„ View Raw YAML

Loading supporting content…

Download this section (compressed HTML)