Department of Clinical and Experimental Medicine, University of Pisa, 56124 Pisa, Italy.
J Clin Endocrinol Metab. 2013 Jul;98(7):2800-10. doi: 10.1210/jc.2012-4029. Epub 2013 Apr 30.
The molecular pathogenesis of primary hyperparathyroidism is still largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene has a major role in the pathogenesis of familial isolated pituitary adenoma.
We evaluated the involvement of the AIP gene in sporadic parathyroid adenomas.
We performed direct sequencing and multiplex ligation-dependent probe amplification analyses of the AIP gene in a large series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP locus was studied, and aryl hydrocarbon receptor interacting protein immunostaining was also performed. In addition, alterations in the MEN1 gene were studied.
A somatic AIP mutation, substitution of arginine with glutamine at codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline in both cases despite the nonfamilial presentation. Heterozygous AIP large deletions were detected in 29 cases including 1 of the 2 mutated tumors, confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at the MEN1 locus, which often shared LOH at the AIP locus, was found in one third of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1 patient.
The AIP gene is rarely involved in parathyroid adenomas, but the germline nature of the mutations suggests that it might predispose to primary hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of sporadic parathyroid adenomas.
原发性甲状旁腺功能亢进的分子发病机制在很大程度上仍然未知。芳香烃受体相互作用蛋白（AIP）基因在家族性孤立性垂体腺瘤的发病机制中起主要作用。
我们评估了 AIP 基因在散发性甲状旁腺腺瘤中的作用。
我们对一大系列散发性甲状旁腺腺瘤进行了 AIP 基因的直接测序和多重连接依赖性探针扩增分析。研究了 AIP 基因座的杂合性丢失（LOH），并进行了芳香烃受体相互作用蛋白免疫染色。此外，还研究了 MEN1 基因的改变。
在 132 个肿瘤中，发现了 2 个肿瘤存在 AIP 基因的体细胞突变，即密码子 304 的精氨酸被谷氨酰胺取代（R304Q）。尽管表现为非家族性，但这两个病例均为胚系突变。在包括 1 个突变肿瘤在内的 29 个病例中检测到 AIP 大片段缺失，证实了 AIP 基因的双等位基因失活。与正常甲状旁腺相比，具有 LOH 的 AIP 突变肿瘤的 AIP 免疫染色减少。在三分之一的肿瘤中发现 MEN1 基因座的 LOH，该基因座通常与 AIP 基因座的 LOH 共享。在 2 个 AIP 突变肿瘤中的 1 个和 22 个甲状旁腺腺瘤中发现了体细胞 MEN1 突变。此外，多重连接依赖性探针扩增分析显示 1 例患者存在 MEN1 基因的 1 个大片段缺失。
AIP 基因很少参与甲状旁腺腺瘤，但突变的胚系性质表明它可能导致原发性甲状旁腺功能亢进。MEN1 基因改变在很大一部分散发性甲状旁腺腺瘤中发生。
