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In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism

Lookup NU author(s): Dr Richard Quinton



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 The authors. OBJECTIVE: Mutations 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 METHODS: Observational, 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. RESULTS: 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 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. CONCLUSIONS: 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.

Publication metadata

Author(s): Salvatori R, Radian S, Diekmann Y, Iacovazzo D, David A, Gabrovska P, Grassi G, Bussell A-M, Stals K, Weber A, Quinton R, Crowne EC, Corazzini V, Metherell L, Kearney T, Du Plessis D, Sinha AK, Baborie A, Lecoq A-L, Chanson P, Ansorge O, Ellard S, Trainer PJ, Balding D, Thomas MG, Korbonits M

Publication type: Article

Publication status: Published

Journal: European journal of endocrinology

Year: 2017

Volume: 177

Issue: 3

Pages: 257-266

Print publication date: 01/09/2017

Online publication date: 20/06/2017

Acceptance date: 19/06/2017

Date deposited: 25/10/2017

ISSN (print): 0804-4643

ISSN (electronic): 1479-683X

Publisher: BioScientifica


DOI: 10.1530/EJE-17-0293

PubMed id: 28634279


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