Abstract
ObjectiveMutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events.Design and methodsObservational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments.ResultsNine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability.ConclusionsThe c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability.
Highlights
The majority of pituitary adenomas are sporadic, they co-occur in families in about 2–5% of the cases (1)
One asymptomatic male patient (UK FIPA 1), identified prospectively after genetic screening, had a GH-secreting pituitary microadenoma (IGF-1 = 1.5 × upper limit of normal) and a 1 cm gastrointestinal stromal tumor; after three years of medical therapy, his pituitary adenoma was successfully operated on, while he remains under surveillance for the gastrointestinal stromal tumor
aryl hydrocarbon receptor-interacting protein (AIP) mutations are reported in about 20% of FIPA pedigrees (1, 27), but a higher percentage has been observed in homogenous acromegaly families
Summary
The majority of pituitary adenomas are sporadic, they co-occur in families in about 2–5% of the cases (1). They form a part of multi-glandular tumor syndromes, such as MEN1 or Carney complex. These families present with isolated pituitary adenomas (familial isolated pituitary adenoma (FIPA) syndrome). A significant proportion (~20%) of these pedigrees carry one of a variety of heterozygous alleles in the aryl hydrocarbon receptor-interacting protein gene (AIP, MIM: 60555) (2, 3). AIP acts as a tumor suppressor gene, requiring a second somatic hit affecting the wild-type (WT) allele, with loss of heterozygosity identified in a number of cases (6, 8, 9)
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