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      Characterization of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Mutations in Familial Isolated Pituitary Adenoma Families

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          Familial isolated pituitary adenoma (FIPA) is an autosomal dominant condition with variable genetic background and incomplete penetrance. Germline mutations of the aryl hydrocarbon receptor interacting protein ( AIP) gene have been reported in 15–40% of FIPA patients. Limited data are available on the functional consequences of the mutations or regarding the regulation of the AIP gene. We describe a large cohort of FIPA families and characterize missense and silent mutations using minigene constructs, luciferase and β-galactosidase assays, as well as in silico predictions. Patients with AIP mutations had a lower mean age at diagnosis (23.6±11.2 years) than AIP mutation-negative patients (40.4±14.5 years). A promoter mutation showed reduced in vitro activity corresponding to lower mRNA expression in patient samples. Stimulation of the protein kinase A-pathway positively regulates the AIP promoter. Silent mutations led to abnormal splicing resulting in truncated protein or reduced AIP expression. A two-hybrid assay of protein–protein interaction of all missense variants showed variable disruption of AIP-phosphodiesterase-4A5 binding. In summary, exonic, promoter, splice-site, and large deletion mutations in AIP are implicated in 31% of families in our FIPA cohort. Functional characterization of AIP changes is important to identify the functional impact of gene sequence variants. Hum Mutat 31:1–11, 2010. © 2010 Wiley-Liss, Inc.

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          Most cited references 46

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          Protein structure prediction on the Web: a case study using the Phyre server.

          Determining the structure and function of a novel protein is a cornerstone of many aspects of modern biology. Over the past decades, a number of computational tools for structure prediction have been developed. It is critical that the biological community is aware of such tools and is able to interpret their results in an informed way. This protocol provides a guide to interpreting the output of structure prediction servers in general and one such tool in particular, the protein homology/analogy recognition engine (Phyre). New profile-profile matching algorithms have improved structure prediction considerably in recent years. Although the performance of Phyre is typical of many structure prediction systems using such algorithms, all these systems can reliably detect up to twice as many remote homologies as standard sequence-profile searching. Phyre is widely used by the biological community, with >150 submissions per day, and provides a simple interface to results. Phyre takes 30 min to predict the structure of a 250-residue protein.
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            TPR proteins: the versatile helix.

            Tetratrico peptide repeat (TPR) proteins have several interesting properties, including their folding characteristics, modular architecture and range of binding specificities. In the past five years, many 3D structures of TPR domains have been solved, revealing at a molecular level the versatility of this basic fold. Here, we discuss the structure of TPRs and highlight the diversity of arrangements and functions that are associated with these ubiquitous domains. Genomic analyses of the distribution of TPR domains are presented along with implications for protein engineering.
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              Medical progress: Acromegaly.

               Shlomo Melmed (2006)

                Author and article information

                Hum Mutat
                Human Mutation
                Wiley Subscription Services, Inc., A Wiley Company
                August 2010
                : 31
                : 8
                : 950-960
                [1 ]simpleDepartment of Endocrinology, Barts and the London School of Medicine, Queen Mary University of London London, United Kingdom
                [2 ]simpleComprehensive Cancer Center, University of Alabama Birmingham, Alabama
                [3 ]simpleDepartment of Molecular Genetics, Royal Devon and Exeter Foundation Trust Exeter, United Kingdom
                [4 ]simpleDepartment of Endocrinology, UCL Medical School, Royal Free Campus London, United Kingdom
                [5 ]simpleNorth East Thames Regional Genetics Service, Great Ormond Street Hospital London, WC1N 3JH, United Kingdom
                Author notes
                *Correspondence to: Márta Korbonits, Queen Mary University of London, Barts & The London School of Medicine, Department of Endocrinology, Charterhouse Square, London, UK, EC1M 6BQ. E-mail: m.korbonits@

                Communicated by Georgia Chenevix-Trench

                Additional Supporting Information may be found in the online version of this article.


                These authors contributed equally to this work.


                See list of consortium members in Appendix.

                Copyright © 2010 Wiley-Liss, Inc., A Wiley Company

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Research Article

                Human biology

                fipa, aip, acromegaly, pituitary adenoma, tumor suppressor


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