Salvatori Roberto, Radian Serban, Diekmann Yoan, Iacovazzo Donato, David Alessia, Gabrovska Plamena, Grassi Giorgia, Bussell Anna-Marie, Stals Karen, Weber Astrid, Quinton Richard, Crowne Elizabeth C, Corazzini Valentina, Metherell Lou, Kearney Tara, Du Plessis Daniel, Sinha Ajay Kumar, Baborie Atik, Lecoq Anne-Lise, Chanson Philippe, Ansorge Olaf, Ellard Sian, Trainer Peter J, Balding David, Thomas Mark G, Korbonits Márta
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
Eur J Endocrinol. 2017 Sep;177(3):257-266. doi: 10.1530/EJE-17-0293. Epub 2017 Jun 20.
Mutations in the aryl hydrocarbon receptor-interacting protein () 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.
Observational, inferential and experimental study, including: mutation testing; reconstruction of 14 -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.
Nine 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 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.
The 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.
