Functional validation of a novel AAAS variant in an atypical presentation of Allgrove syndrome.
achalasia
alacrima
aladin
allgrove
whole-exome sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
30
03
2022
received:
29
10
2021
accepted:
03
05
2022
pubmed:
17
5
2022
medline:
14
7
2022
entrez:
16
5
2022
Statut:
ppublish
Résumé
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. 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. 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. Review of the patient's clinical, pathological, and genetic findings resulted in a diagnosis of Triple A syndrome.
Sections du résumé
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.
Identifiants
pubmed: 35570467
doi: 10.1002/mgg3.1966
pmc: PMC9266593
doi:
Substances chimiques
AAAS protein, human
0
Nerve Tissue Proteins
0
Nuclear Pore Complex Proteins
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1966Informations de copyright
© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
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