Affinage

AAAS

Aladin · UniProt Q9NRG9

Length
546 aa
Mass
59.6 kDa
Annotated
2026-04-28
47 papers in source corpus 7 papers cited in narrative 7 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALADIN, encoded by AAAS, is a 546-amino-acid WD-repeat nucleoporin that localizes to the nuclear pore complex (NPC), where it participates in nucleocytoplasmic transport (PMID:11159947, PMID:18628786). The C-terminal domain of ALADIN is essential for its correct targeting to the NPC; most disease-causing mutations mislocalize the protein to the cytoplasm or nucleus, abolishing function, although certain missense mutations (e.g., L430F) retain NPC localization but impair function at the pore (PMID:31939195, PMID:18628786, PMID:20200814). Loss-of-function mutations in AAAS cause Triple A (Allgrove) syndrome, a multisystem disorder characterized by adrenal insufficiency, achalasia, and alacrima, consistent with the gene's predominant expression in neuroendocrine and gastrointestinal tissues (PMID:11159947, PMID:11701718).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2001 High

    Positional cloning identified AAAS as the causative gene for Triple A syndrome, establishing that it encodes a novel WD-repeat protein (ALADIN) with predominant expression in the neuroendocrine and gastrointestinal tissues affected in the disease.

    Evidence Positional cloning, mutation screening of patient cohorts, and RNA blotting in human tissues

    PMID:11159947 PMID:11701718

    Open questions at the time
    • Subcellular localization of ALADIN was not yet determined
    • The molecular function of ALADIN beyond its WD-repeat architecture was unknown
    • How loss of ALADIN leads to tissue-specific disease manifestations was unresolved
  2. 2008 Medium

    Demonstration that ALADIN localizes to the nuclear pore complex established it as a nucleoporin, and the finding that the L430F mutant retains NPC localization showed that mislocalization is not the only disease mechanism — some mutations impair function at the pore itself.

    Evidence GFP-fusion transfection and fluorescence microscopy in cultured cells

    PMID:18628786

    Open questions at the time
    • The specific NPC-associated function disrupted by L430F was not identified
    • Which NPC subcomplex ALADIN associates with was not defined
    • No cargo molecules whose import or export depends on ALADIN were identified
  3. 2010 Medium

    Systematic localization studies of mutant ALADIN proteins showed that most pathogenic mutations cause mislocalization away from the NPC to the cytoplasm or nucleus, establishing mislocalization as the predominant disease mechanism.

    Evidence Cellular localization studies of multiple ALADIN mutants

    PMID:20200814

    Open questions at the time
    • Whether mislocalized ALADIN retains any partial function was not tested
    • The structural basis for NPC targeting was not resolved
    • No quantitative nucleocytoplasmic transport assay was applied
  4. 2016 Medium

    Characterization of a splice-site mutation demonstrated that a single nucleotide change can produce multiple aberrant transcripts, each leading to frameshifts and premature termination, clarifying how non-coding mutations disrupt ALADIN protein integrity.

    Evidence RT-PCR, sequencing, and in silico splice site analysis of patient-derived RNA

    PMID:27414811

    Open questions at the time
    • Whether truncated proteins are produced or degraded by NMD was not directly assessed
    • Functional consequences at the protein level were inferred, not measured
  5. 2020 Medium

    Transcript and expression studies of truncating variants pinpointed the C-terminal domain as essential for NPC targeting, providing the first domain-level requirement for ALADIN localization.

    Evidence Transcript analysis and expression studies in cells with truncating AAAS variants

    PMID:31939195

    Open questions at the time
    • Minimal C-terminal sequence sufficient for NPC targeting was not defined
    • Direct binding partners mediating C-terminal-dependent NPC anchoring were not identified
  6. 2022 Medium

    Functional validation of the p.(Arg270Pro) variant demonstrated decreased NPC localization, extending the genotype–localization correlation to a novel pathogenic missense mutation within the WD-repeat domain.

    Evidence Cellular localization assay in cells expressing patient-derived ALADIN variant

    PMID:35570467

    Open questions at the time
    • No high-resolution structural model of ALADIN at the NPC exists
    • How Arg270 contributes to WD-repeat folding or NPC binding was not mechanistically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific nucleocytoplasmic transport cargoes regulated by ALADIN and the molecular mechanism by which ALADIN loss leads to the tissue-specific pathology of Triple A syndrome remain unknown.
  • No transport cargo dependent on ALADIN has been identified in the primary literature
  • The NPC subcomplex to which ALADIN is anchored has not been defined
  • How ALADIN dysfunction selectively damages adrenal, esophageal, and lacrimal tissues is unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005635 nuclear envelope 4
Pathway
R-HSA-9609507 Protein localization 3

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 AAAS encodes a novel WD-repeat protein (ALADIN, 546 amino acids) whose loss-of-function mutations cause Triple A syndrome; RNA blotting showed marked expression in neuroendocrine and gastrointestinal structures predominantly affected in the disease, identifying AAAS as the causative gene. Positional cloning, mutation analysis in patients, RNA blotting Human molecular genetics High 11159947
2001 AAAS mutations (including splice donor, nonsense, and missense variants) cause loss of function of the ALADIN protein and underlie Allgrove syndrome; mutations predicted to disrupt WD-repeat formation or beta-strand stability were identified, establishing structure-function relationships in ALADIN. Sequencing of AAAS gene, structural prediction of WD-repeat domains The Journal of clinical endocrinology and metabolism Medium 11701718
2008 The ALADIN(L430F) missense mutation correctly localizes to nuclear pore complexes (NPCs) as shown by GFP-fusion transfection experiments, indicating this mutation impairs ALADIN function at the NPC without disrupting its localization. GFP-fusion transfection and fluorescence microscopy European journal of human genetics : EJHG Medium 18628786
2010 Mutant ALADIN proteins can mislocalize to the cytoplasm and/or nucleus rather than the nuclear pore complex, resulting in impaired protein function; this mislocalization is a general mechanism by which AAAS mutations cause disease. Cellular localization studies of mutant ALADIN Experimental and clinical endocrinology & diabetes Medium 20200814
2016 The splice site mutation c.1331+1G>A in AAAS abolishes the exon 14 splice donor site and activates a cryptic intronic splice site, producing two aberrant transcripts (exon 14 skipping alone, and concurrent exon 14 skipping plus 99 bp intron 14 retention), both causing frameshifts with premature stop codons, demonstrating how a single splice mutation disrupts ALADIN protein structure. RT-PCR, sequencing, in silico splice site analysis Hormone research in paediatrics Medium 27414811
2020 The C-terminal domain of ALADIN is essential for its correct targeting to the nuclear pore complex and protein function, as demonstrated by transcript analysis and expression studies of truncating variants affecting this region. Transcript analysis, expression studies in cells Journal of endocrinological investigation Medium 31939195
2022 The novel ALADIN missense variant p.(Arg270Pro) demonstrates decreased localization to the nuclear pore complex in cells expressing the variant, functionally validating its pathogenicity in Triple A syndrome. Cellular localization assay (nuclear pore targeting) in patient-variant expressing cells Molecular genetics & genomic medicine Medium 35570467

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy. Arteriosclerosis, thrombosis, and vascular biology 228 26044582
2001 Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Human molecular genetics 192 11159947
2008 Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 92 18451329
2001 Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin. The Journal of clinical endocrinology and metabolism 58 11701718
2002 Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation. Neurology 49 11914417
2004 Triple-A syndrome with prominent ophthalmic features and a novel mutation in the AAAS gene: a case report. BMC ophthalmology 33 15217518
2008 Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation. European journal of pediatrics 24 18172684
2008 Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe. European journal of human genetics : EJHG 24 18628786
2002 Analysis of the AAAS gene in a Japanese patient with triple A syndrome. Endocrine journal 17 12008750
2006 A novel AAAS gene mutation (p.R194X) in a patient with triple A syndrome. Hormone research 15 16543750
2006 Allgrove syndrome with features of familial dysautonomia: a novel mutation in the AAAS gene. Acta paediatrica (Oslo, Norway : 1992) 15 16938764
2004 Two cases of Allgrove syndrome with mutations in the AAAS gene. Endocrine journal 15 15516781
2003 Three children with triple A syndrome due to a mutation (R478X) in the AAAS gene. Hormone research 14 14646395
2007 An Alu-mediated rearrangement causing a 3.2kb deletion and a novel two base pair deletion in AAAS gene as the cause of triple A syndrome. Molecular genetics and metabolism 12 17911039
2004 Phenotypic heterogeneity in AAAS gene mutation. Acta paediatrica (Oslo, Norway : 1992) 12 15384895
2022 Expression of a PCSK9 Gain-of-Function Mutation in C57BL/6J Mice to Facilitate Angiotensin II-Induced AAAs. Biomolecules 11 35883473
2015 Identification of AAAS gene mutation in Allgrove syndrome: A report of three cases. Experimental and therapeutic medicine 11 26622478
2010 Triple A syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency. Journal of the neurological sciences 11 20051279
2009 Triple A or Allgrove syndrome. A case report with ophthalmic abnormalities and a novel mutation in the AAAS gene. Ophthalmic genetics 11 19172511
2011 Mutation spectra of the AAAS gene in Iranian families with Allgrove Syndrome. Archives of medical research 10 21565631
2006 Triple-A syndrome--the first Chinese patient with novel mutations in the AAAS gene. Journal of pediatric endocrinology & metabolism : JPEM 10 16789645
2015 Triple A syndrome with a novel indel mutation in the AAAS gene and delayed puberty. Journal of pediatric endocrinology & metabolism : JPEM 9 25781531
2012 [Allgrove syndrome (triple A). Finding of a mutation not described in the AAAS gene]. Anales de pediatria (Barcelona, Spain : 2003) 8 22824007
2005 Molecular cloning and characterization of AAAS-V2, a novel splice variant of human AAAS. Molecular biology reports 8 16022285
2004 Myoclonus and generalized digestive dysmotility in triple A syndrome with AAAS gene mutation. Movement disorders : official journal of the Movement Disorder Society 8 15022193
2020 Triple A (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy. Hormones (Athens, Greece) 7 32700293
2018 Clinical and molecular report of c.1331 + 1G > A mutation of the AAAS gene in a Moroccan family with Allgrove syndrome: a case report. BMC pediatrics 7 29866068
2016 Splicing Defects in the AAAS Gene Leading to both Exon Skipping and Partial Intron Retention in a Tunisian Patient with Allgrove Syndrome. Hormone research in paediatrics 7 27414811
2012 Lack of significant influence for FcγRIIa-RH131 or hemoglobin AA/AS polymorphisms on immunity and susceptibility to uncomplicated malaria and existence of marked linkage between the two polymorphisms in Daraweesh. Microbes and infection 6 22289203
2009 Triple A syndrome: two novel mutations in the AAAS gene. BMJ case reports 6 21686524
2006 Mutations of the AAAS gene in an Indian family with Allgrove's syndrome. World journal of gastroenterology 6 16937455
2010 Two patients with an identical novel mutation in the AAAS gene and similar phenotype of triple A (Allgrove) syndrome. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association 5 20200814
2005 Familial occurrence of adrenocortical insufficiency in two brothers with Allgrove syndrome. A case report of 4A (Allgrove) syndrome with epilepsy and a new AAAS gene mutation. Neuro endocrinology letters 4 16264411
2023 Triple-A Syndrome in Morocco: Founder Effect, Age Estimation of the AAAS c.1331+1G>A Variant, and Implications for Genetic Diagnosis. Molecular syndromology 3 38585542
2022 Functional validation of a novel AAAS variant in an atypical presentation of Allgrove syndrome. Molecular genetics & genomic medicine 3 35570467
2020 Two novel truncating variants of the AAAS gene causative of the triple A syndrome. Journal of endocrinological investigation 3 31939195
2019 Triple A syndrome: two siblings with a novel mutation in the AAAS gene. Hormones (Athens, Greece) 3 30612286
1992 Contributions to the history of psychology: XC. Evolutionary biology and heritable traits (with reference to oriental-white-black differences): the 1989 AAAS paper. Psychological reports 3 1454929
2019 Homozygous deletion of the entire AAAS gene in a triple A syndrome patient. European journal of medical genetics 2 31071487
2013 Clinical and genetic characterization of a Chinese patient with triple A syndrome and novel compound heterozygous mutations in the AAAS gene. Journal of pediatric endocrinology & metabolism : JPEM 2 23327820
2020 Allgrove Syndrome: A Report of New Pathological Variants in the AAAS Gene. Cornea 1 32073457
2026 Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant in the AAAS gene. Neurogenetics 0 41498959
2025 A triple A syndrome with neurological findings; c464G>A mutation in the AAAS gene. Ideggyogyaszati szemle 0 40476452
2025 A Novel AAAS Gene Mutation in Allgrove Syndrome: Case Report and Genetic Insights from a Chinese Xinjiang Girl. Annals of clinical and laboratory science 0 40962451
2022 [A case of triple A syndrome with c.463C>T mutation in the AAAS gene]. Rinsho shinkeigaku = Clinical neurology 0 36031376
2006 In response to an open invitation for comments on AAAS project 2061's Benchmark books on science. Part 1: documentation of serious errors in cell biology. Physiological chemistry and physics and medical NMR 0 17405412
1988 AAAS Meeting: Science Smorgasbord with Snow. Science (New York, N.Y.) 0 17815694