| Aspect | Key findings for human AAAS/ALADIN (UniProt Q9NRG9) | Strongest evidence type | Representative recent source(s) |
|---|---|---|---|
| Verified molecular identity | **AAAS** encodes **ALADIN**, a **546-aa WD-repeat nucleoporin** of the nuclear pore complex (NPC); recent reviews/methods papers describe **7 WD repeats** and broad expression with enrichment in adrenal/pituitary/CNS/GI-related tissues, matching the UniProt human target Q9NRG9 rather than another gene symbol usage (pqac-00000020, pqac-00000024) | Review; iPSC/model background | Hasenmajer et al., **Feb 2023**, *Rev Endocr Metab Disord*, https://doi.org/10.1007/s11154-023-09784-7 (pqac-00000020); Ruiz-Babot et al., **Nov 2023**, *Cell Reports Methods*, https://doi.org/10.1016/j.crmeth.2023.100627 (pqac-00000024) |
| Primary localization | ALADIN localizes to the **NPC/nuclear envelope**; proper NE/NPC targeting is **NDC1-dependent**. NDC1 variants that disrupt the ALADIN-binding region reduce ALADIN recruitment to the NE, and ALADIN is reported as **anchored via NDC1 rather than POM121/GP210** (pqac-00000003, pqac-00000007, pqac-00000019, pqac-00000030) | Structural/cell assay with patient fibroblasts | Smits et al., **Oct 2024**, *Hum Genet Genomics Adv*, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000003, pqac-00000007, pqac-00000030) |
| Key interaction partner: NDC1 | NDC1 is the principal membrane anchor recruiting ALADIN to the NPC; structural modeling places NDC1 C-terminal residues in direct interface with ALADIN, and disease-associated NDC1 alleles impair ALADIN localization and NPC assembly/post-mitotic insertion (pqac-00000001, pqac-00000007) | Structural modeling + patient fibroblast assay | Smits et al., **Oct 2024**, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000001, pqac-00000007) |
| Other NPC-related partners | Recent literature also places ALADIN in a network including **NUP155** in addition to NDC1; proteomic/NPC studies support ALADIN as a bona fide NPC component mislocalized in triple A syndrome (pqac-00000001, pqac-00000002) | Review; NPC interaction mapping | Smits et al., **Oct 2024**, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000001); Braun et al., **Apr 2026**, https://doi.org/10.1007/s00018-026-06220-2 (pqac-00000002) |
| Cargoes/processes affected: DNA repair proteins | A key mechanistic model is **selective nuclear import failure**: mutant ALADIN reduces nuclear import of **DNA ligase I** and **aprataxin**, proteins needed for repair of DNA single-strand breaks, linking AAAS dysfunction to genome maintenance defects (pqac-00000004, pqac-00000014, pqac-00000024) | Mechanistic review of primary studies | Cehic et al., **Sep 2024**, *Front Endocrinol*, https://doi.org/10.3389/fendo.2024.1431383 (pqac-00000014); Ruiz-Babot et al., **Nov 2023**, https://doi.org/10.1016/j.crmeth.2023.100627 (pqac-00000024) |
| Cargoes/processes affected: ferritin heavy chain | ALADIN dysfunction also impairs nuclear import of **ferritin heavy chain (FTH1)**, a protective factor against nuclear oxidative damage; this supports the widely cited model that **oxidative stress susceptibility** is central to AAAS pathology (pqac-00000001, pqac-00000004, pqac-00000015, pqac-00000019, pqac-00000024) | Cell/mechanistic assay summarized by recent review | Smits et al., **Oct 2024**, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000001, pqac-00000019); Cehic et al., **Sep 2024**, https://doi.org/10.3389/fendo.2024.1431383 (pqac-00000015) |
| Core molecular function | Best-supported current interpretation: ALADIN is a **scaffold/selective transport regulator at the NPC**, not an enzyme or transporter with a defined small-molecule substrate. Its primary role is to enable **proper nucleocytoplasmic trafficking of selected protein cargos**, thereby supporting **DNA repair**, **redox homeostasis**, and tissue-specific functions in adrenal and neural cells (pqac-00000000, pqac-00000014, pqac-00000024) | Review synthesis + disease modeling | Cehic et al., **Sep 2024**, https://doi.org/10.3389/fendo.2024.1431383 (pqac-00000014); Ruiz-Babot et al., **Nov 2023**, https://doi.org/10.1016/j.crmeth.2023.100627 (pqac-00000024) |
| Redox / oxidative stress role | Multiple recent sources summarize increased **ROS/oxidative stress** in AAAS-deficient contexts; ALADIN loss alters oxidative-stress responses in fibroblasts/adrenal cells, and antioxidant response has been proposed as a therapeutic angle in isolated reports (pqac-00000001, pqac-00000015, pqac-00000017, pqac-00000018) | Case-review synthesis; cell assay summaries | Cehic et al., **Sep 2024**, https://doi.org/10.3389/fendo.2024.1431383 (pqac-00000015, pqac-00000017, pqac-00000018); Smits et al., **Oct 2024**, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000001) |
| Steroidogenesis / adrenal pathway | AAAS dysfunction is linked to **adrenal steroidogenic failure**. In patient adrenal tissue, **SCARB1** transcript is reduced, **MC2R** is strongly reduced, and **phospho-PKA** shows decreased nuclear and increased cytosolic localization, consistent with impaired **cAMP/PKA-dependent nuclear signaling** and ACTH resistance (pqac-00000008, pqac-00000010, pqac-00000011, pqac-00000029) | Patient tissue study | Bitetto et al., **Jun 2023**, *Orphanet J Rare Dis*, https://doi.org/10.1186/s13023-023-02763-w (pqac-00000008, pqac-00000010, pqac-00000011) |
| Human cell disease modeling | CRISPR-engineered **AAAS-null iPSC-derived steroidogenic cells** recapitulate adrenal insufficiency features, showing **significantly lower cortisol, cortisone, corticosterone, and aldosterone** secretion than controls; this is a direct 2023 implementation for functional modeling of AAAS-associated disease (pqac-00000013, pqac-00000022, pqac-00000024, pqac-00000028) | iPSC disease model | Ruiz-Babot et al., **Nov 2023**, https://doi.org/10.1016/j.crmeth.2023.100627 (pqac-00000013, pqac-00000022, pqac-00000024, pqac-00000028) |
| Disease association | Biallelic AAAS variants cause **triple A (Allgrove) syndrome**, classically comprising **alacrima, achalasia, and adrenal insufficiency**, often with neurologic/autonomic involvement; ALADIN mislocalization from the NPC is a common pathogenic theme (pqac-00000014, pqac-00000020) | Review | Hasenmajer et al., **Feb 2023**, https://doi.org/10.1007/s11154-023-09784-7 (pqac-00000020); Cehic et al., **Sep 2024**, https://doi.org/10.3389/fendo.2024.1431383 (pqac-00000014) |
| Key 2023–2024 clinical statistics | Recent reviews/case analyses report: **complete triad ~70%**; **alacrima >90%** or **90–100%**; **achalasia 75–85%**; **primary adrenal insufficiency almost 85%**; **neurologic involvement ~60% to two-thirds**; **AAAS variants in ~90% of patients** in one 2023 review; disease prevalence cited as about **1 in 1,000,000** in review literature (pqac-00000014, pqac-00000018, pqac-00000020, pqac-00000021, pqac-00000000) | Review; case-review synthesis | Hasenmajer et al., **Feb 2023**, https://doi.org/10.1007/s11154-023-09784-7 (pqac-00000020, pqac-00000021); Cehic et al., **Sep 2024**, https://doi.org/10.3389/fendo.2024.1431383 (pqac-00000014, pqac-00000018) |
| Notable genotype/phenotype data | In a 2024 genotype-focused summary, the **p.Ser263Pro** AAAS variant showed neurologic manifestations in **33/34 (97.1%)** carriers versus **133/172 (77.3%)** in other genotypes (**p = 0.006**); possible Slavic founder effect noted (**25/36, 69.4%**) (pqac-00000005) | Cohort/genotype-phenotype analysis | Juścińska et al., **Jan 2026** reporting aggregate cohort data, https://doi.org/10.1007/s10048-025-00870-3 (pqac-00000005) |
| Recent clinical implementation | Current real-world use is mainly **molecular diagnosis and mechanistic stratification** of rare disease: recent Sudanese series identified **6 AAAS mutations in 20 families/31 patients**, including novel alleles, emphasizing early genetic diagnosis to prevent adrenal crises; NDC1 analysis expands differential diagnosis to **triple A-like syndromes** when AAAS is negative (pqac-00000001) | Case series / genetic diagnostics | Smits et al., **Oct 2024**, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000001) |
| Visual/mechanistic support from recent figure | A recent figure shows **reduced ALADIN nuclear-envelope staining** in NDC1-variant fibroblasts and **lower post-mitotic NPC density** in patient cells, visually supporting the ALADIN-at-NPC recruitment model (pqac-00000030) | Figure-based cell assay | Smits et al., **Oct 2024**, Figure 4 context, https://doi.org/10.1016/j.xhgg.2024.100327 (pqac-00000030) |


*Table: This table condenses the most relevant verified facts about human AAAS/ALADIN, including identity, NPC localization, interaction partners, mechanisms, disease links, and recent 2023–2024 studies. It is designed as a quick-reference artifact for functional annotation and evidence-weighted interpretation.*