Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism
Novel intronic mutation of MEN1 gene causing familial isolated primary hyperparathyroidism
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DOI：
10.1210/jc.2003-032101
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发表时间：
2004-08-01
影响因子：
5.8
通讯作者：
Fardella, CE
中科院分区：
文献类型：
--
作者：
Carrasco, CA;González, AA;Fardella, CE
原发性甲状旁腺功能亢进可能作为遗传性综合征的一部分发生，包括多发性内分泌腺瘤1型和2A型（MEN 1和MEN 2A）、甲状旁腺功能亢进-颌肿瘤综合征和家族性孤立性甲状旁腺功能亢进（FIHP）。目前还不清楚FIHP是否对应于MEN 1的不同遗传实体或变体（或甲状旁腺功能亢进-颌骨肿瘤综合征）。我们报告一个病人和11个家庭成员与FIHP中，我们发现了一个杂合G到A突变的肿瘤抑制基因MEN 1的核苷酸7361。该突变位于内含子9的第一个碱基（IVS 9 + 1 G>A）。所有的甲状旁腺功能亢进的家庭成员是杂合子的内含子突变。在COS细胞中进行体外研究，转染携带编码区跨越外显子-内含子9和10的突变体和野生型序列的小基因。RT-PCR分析显示，在突变的MEN 1基因中，异常mRNA的大小（829 bp）大于正常转录本（629 bp）。较长的PCR产物包括外显子9、未剪接的内含子9和部分外显子10。从患者血液中提取的MEN 1 mRNA的RT-PCR证实了成熟mRNA中未剪接内含子9的存在。总之，我们报告一例与MEN 1基因的一个新的内含子杂合种系突变（IVS 9 + 1 G> A）相关的FIHP。这种突变产生mRNA的异常剪接，可能导致截短的蛋白质，没有活性，解释了该患者及其家人的临床表现。
Primary hyperparathyroidism may occur as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2A (MEN1 and MEN2A), hyperparathyroidism-jaw tumor syndrome, and the familial isolated hyperparathyroidism (FIHP). It is unclear whether FIHP corresponds to a different genetic entity or a variant of MEN1 ( or hyperparathyroidism-jaw tumor syndrome). We report a patient and 11 family members with FIHP in whom we identified a heterozygous G-to-A mutation at nucleotide 7361 of tumor suppressor MEN1 gene. This mutation is located in the first base of intron 9 (IVS9 + 1 G>A). All the family members with hyperparathyroidism were heterozygous for the intronic mutation. In vitro studies were performed in COS cells transfected with minigenes carrying the coding regions spanning exon-intron 9 and 10 with the mutant and the wild-type sequences. RT-PCR analyses showed an abnormal mRNA of greater size ( 829 bp) in the mutated MEN1 gene than the normal transcript ( 629 bp). The longer PCR product includes the exon 9, the unspliced intron 9, and part of exon 10. RT-PCR of MEN1 mRNA from patient's blood confirmed the existence of unspliced intron 9 in mature mRNA. In summary, we report a case of FIHP associated with a new intronic heterozygous germline mutation (IVS9 + 1 G> A) of MEN1 gene. This mutation produces an aberrant splicing of mRNA that could lead to a truncated protein, without activity, explaining the clinical picture of this patient and his family.