The genetic basis of triple A (Allgrove) syndrome in a Greek family.
Triple A (or Allgrove) syndrome is an autosomal recessive genetic disorder. Patients typically suffer from chronic adrenal insufficiency due to resistance to ACTH (Addison's disease), achalasia of the cardia, and defective tear formation (alacrima). The syndrome is caused by mutations in the AAAS gene which encodes the protein ALADIN, a constituent of eukaryotic nuclear pore complexes. The multi-systemic nature and variable manifestations of the triple A syndrome often confound its diagnosis and limit our understanding of its exact pathogenesis. We performed mutational screening of the AAAS gene in a Greek family of four individuals, including an affected propositus with typical symptoms of late-onset triple A syndrome. Our results are consistent with an autosomal recessive pattern of inheritance within the family, caused by a functional c.43C>A mutation in exon 1 of the AAAS gene. All members of the family were also homozygous for a silent c.855C>T nucleotide change within exon 9 of the AAAS gene, representing a common single nucleotide polymorphism. The compromising c.43C>A mutation is predicted to cause a p.Gln15Lys amino acid substitution in the ALADIN protein. However, it has been suggested that the functional impact of this mutation may be more severe, causing a shift in the reading frame of AAAS gene via formation of an aberrant premature donor splice site within exon 1. We propose that mutational analysis of the AAAS gene should be considered in adult patients with one or more clinical signs of the disease, as diagnosis of late-onset cases can be ambiguous.
School of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.
Labrini
L
Papageorgiou
Konstantinos
K
Mimidis
Katerina R
KR
Katsani
Giannoulis
G
Fakis
D000309:Adrenal Insufficiency / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000328:Adult; D019943:Amino Acid Substitution; D004931:Esophageal Achalasia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005190:Family; D005260:Female; D016368:Frameshift Mutation; D006115:Greece; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D022821:RNA Splice Sites
C416506:AAAS protein, human; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins; D022821:RNA Splice Sites