Mutant WD-repeat protein in triple-A syndrome

Topic: Brain proteins, microglia and lab models

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals.

@article{tulliopelet2000-11062474,
  author  = {Tullio-Pelet, A. and Salomon, R. and Hadj-Rabia, S. and Mugnier, C. and de Laet, M. H. and Chaouachi, B. and Bakiri, F. and Brottier, P. and others},
  title   = {{Mutant WD-repeat protein in triple-A syndrome}},
  journal = {Nature genetics},
  year    = {2000},
  doi     = {10.1038/81642},
  pmid    = {11062474},
  url     = {https://doi.org/10.1038/81642}
}

Key findings

• Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well.
• Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals.
• We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago.
• The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome.

Why it matters

This study identified a novel gene (AAAS) that is mutant in individuals with triple-A syndrome, a rare autosomal recessive disorder that can include late-onset mild dementia among its neurological symptoms. It is genetic research into a rare syndrome and does not provide a treatment, cure, or prevention for Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/81642
• PubMed: 11062474
• Original source →

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