Functional validation of a novel AAAS variant in an atypical presentation of Allgrove syndrome

Erica L. Macke, Joel A. Morales-Rosado, Sarah K. Macklin-Mantia, Christopher T. Schmitz, Björn Oskarsson, Eric W. Klee, Klaas J. Wierenga

Research output: Contribution to journalArticlepeer-review


Background: Achalasia-addisonianism-alacrima syndrome, frequently referred to as Allgrove syndrome or Triple A syndrome, is a multisystem disorder resulting from homozygous or compound heterozygous pathogenic variants in the gene encoding aladin (AAAS). Aladin is a member of the WD-repeat family of proteins and is a component of the nuclear pore complex. It is thought to be involved in nuclear import and export of molecules. Here, we describe an individual with a paternally inherited truncating variant and a maternally inherited, novel missense variant in AAAS presenting with alacrima, achalasia, anejaculation, optic atrophy, muscle weakness, dysarthria, and autonomic dysfunction. Methods: Whole-exome sequencing was performed in the proband, sister, and parents. Variants were confirmed by Sanger sequencing. The localization of aladin to the nuclear pore was assessed in cells expressing the patient variant. Results: Functional testing of the maternally inherited variant, p.(Arg270Pro), demonstrated decreased localization of aladin to the nuclear pore in cells expressing the variant, indicating a deleterious effect. Follow-up testing in the proband's affected sister revealed that she also inherited the biallelic AAAS variants. Conclusions: Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome.

Original languageEnglish (US)
Article numbere1966
JournalMolecular Genetics and Genomic Medicine
Issue number7
StatePublished - Jul 2022


  • achalasia
  • alacrima
  • aladin
  • allgrove
  • whole-exome sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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