FRA10AC1

FRA10AC1 encodes a conserved nucleoplasmic protein that functions as a peripheral component of the spliceosomal C complex (PMID:15203205, PMID:34694367). Within the spliceosome it directly engages the non-core component DGCR14/ESS2, an interaction confirmed by reciprocal co-immunoprecipitation at endogenous protein stoichiometries and refined by domain mapping; under endogenous conditions it does not associate with the core component SF3B2 or with CHERP, NKAP, or RED (PMID:34694367, PMID:36980839). Loss of FRA10AC1 does not rescue missplicing caused by mutations at conserved 5' and 3' splice-site dinucleotides, indicating it is not required for this aspect of splice-site recognition and that its specific catalytic or regulatory role in splicing remains undefined (PMID:34694367). Transcription of FRA10AC1 is silenced by expansion and methylation of a CGG repeat in its 5'UTR at the FRA10A fragile site (PMID:15203205), and biallelic loss-of-function variants—including a stability-impairing in-frame deletion and splice-site variants that truncate the protein—cause a neurodevelopmental syndrome with growth retardation through reduced or absent transcript and protein (PMID:34694367, PMID:41571908).

1. 2004 Medium

   Establishing where FRA10AC1 acts and how the FRA10A fragile site disrupts it answered whether this gene product is nuclear and how repeat expansion silences it.

   Evidence Immunofluorescence of EGFP-tagged FRA10AC1, methylation analysis, and allele-specific expression assays

   PMID:15203205

   Open questions at the time

   • Localization shown only for an overexpressed EGFP fusion, not endogenous protein
   • No molecular function or interaction partner identified at this stage
2. 2022 High

   Placing FRA10AC1 in the spliceosomal C complex and identifying DGCR14 as a specific partner answered what macromolecular machine the protein belongs to and which component it contacts.

   Evidence Co-immunoprecipitation of HA-FRA10AC1 with negative controls, stability assessment of the p.Glu165del variant, and patient-fibroblast western blot/RT-PCR

   PMID:34694367

   Open questions at the time

   • The catalytic or regulatory contribution of FRA10AC1 to splicing not defined
   • DGCR14 interaction not yet domain-mapped at this stage
3. 2022 Medium

   Testing whether FRA10AC1 loss alters splice-site recognition addressed its functional requirement in core splicing, returning a negative that narrows its role.

   Evidence In vitro splicing reporter assay in FRA10AC1-deficient patient fibroblasts

   PMID:34694367

   Open questions at the time

   • Does not identify which splicing events, if any, depend on FRA10AC1
   • Negative result for one assay does not exclude other splicing roles
4. 2023 Medium

   Mapping the FRA10AC1–ESS2 interaction domains and re-testing the SF3B2 association resolved the direct binding partner and excluded a previously reported core-spliceosome contact under endogenous conditions.

   Evidence Co-immunoprecipitation of endogenous proteins, domain mapping, and tissue co-localization analysis

   PMID:36980839

   Open questions at the time

   • Functional consequence of the FRA10AC1–ESS2 interaction unknown
   • Single-lab study without structural confirmation of mapped domains
5. 2026 Medium

   Confirming that a homozygous splice-site variant produces exon skipping and truncation extended the loss-of-function disease mechanism to an additional allele.

   Evidence mRNA RT-PCR confirmation of exon 7 skipping and exome sequencing of a single case

   PMID:41571908

   Open questions at the time

   • Single case without functional rescue
   • Does not connect the molecular splicing role of FRA10AC1 to the disease phenotype

• The precise catalytic or regulatory function of FRA10AC1 within the spliceosomal C complex, and the mechanism linking its loss to neurodevelopmental and growth phenotypes, remain unresolved.
• No defined molecular activity within the spliceosome
• No structural model of FRA10AC1 or its DGCR14/ESS2 contact
• Mechanism connecting splicing role to disease phenotype unestablished