Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.
Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.
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DOI：
10.1002/humu.21292
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发表时间：
2010-08
期刊：
影响因子：
3.9
通讯作者：
Korbonits, Marta
中科院分区：
文献类型：
--
作者：
Igreja, Susana;Chahal, Harvinder S.;King, Peter;Bolger, Graeme B.;Srirangalingam, Umasuthan;Guasti, Leonardo;Chapple, J. Paul;Trivellin, Giampaolo;Gueorguiev, Maria;Guegan, Katie;Stals, Karen;Khoo, Bernard;Kumar, Ajith V.;Ellard, Sian;Grossman, Ashley B.;Korbonits, Marta
家族性孤立性垂体腺瘤（FIPA）是一种常染色体显性遗传疾病，遗传背景多变，发病率不完全。据报道，在15-40%的FIPA患者中存在芳香烃受体相互作用蛋白（AIP）基因的种系突变。关于突变的功能后果或AIP基因的调控的数据有限。我们描述了一个大的FIPA家族队列，并使用微基因构建体、荧光素酶和β-半乳糖苷酶测定以及计算机预测来表征错义和沉默突变。AIP突变患者的平均诊断年龄（23.6±11.2岁）低于AIP突变阴性患者（40.4±14.5岁）。启动子突变显示出与患者样品中较低的mRNA表达相对应的体外活性降低。蛋白激酶A途径的刺激正向调节AIP启动子。沉默突变导致异常剪接，导致截短的蛋白质或减少AIP表达。所有错义变体的蛋白质-蛋白质相互作用的双杂交测定显示AIP-磷酸二酯酶-4A5结合的可变破坏。总之，在我们的FIPA队列中，31%的家庭涉及AIP的外显子、启动子、剪接位点和大缺失突变。AIP变化的功能表征对于鉴定基因序列变体的功能影响是重要的。2010年，Mutat 31：1-11。© 2010 Wiley-Liss公司。
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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