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Whole exome sequencing in familial isolated primary hyperparathyroidism.
Journal of Endocrinological Investigation ( IF 3.9 ) Pub Date : 2019-09-05 , DOI: 10.1007/s40618-019-01107-5
F Cetani 1 , E Pardi 2 , P Aretini 3 , F Saponaro 2 , S Borsari 2 , L Mazoni 2 , M Apicella 2 , P Civita 3 , M La Ferla 3 , M A Caligo 4 , F Lessi 3 , C M Mazzanti 3 , L Torregossa 5 , A Oppo 6 , C Marcocci 2
Affiliation  

PURPOSE Familial isolated hyperparathyroidism (FIHP) is a rare inherited disease accounting for 1% of all cases of primary hyperparathyroidism (PHPT). It is genetically heterogeneous being associated with mutations in different genes, including MEN1, CDC73, CASR, and recently GCM2. The aim of the study was to further investigate the molecular pathogenesis in Italian FIHP kindreds. METHODS We used whole exome sequencing (WES) in the probands of seven unrelated FIHP kindreds. We carried out a separate family-based exome analysis in a large family characterized by the co-occurrence of PHPT with multiple tumors apparently unrelated to the disease. Selected variants were also screened in 18 additional FIHP kindreds. The clinical, biochemical, and pathological characteristics of the families were also investigated. RESULTS Three different variants in GCM2 gene were found in two families, but only one (p.Tyr394Ser), already been shown to be pathogenic in vitro, segregated with the disease. Six probands carried seven heterozygous missense mutations segregating with the disease in the FAT3, PARK2, HDAC4, ITPR2 and TBCE genes. A genetic variant in the APC gene co-segregating with PHPT (p.Val530Ala) was detected in a family whose affected relatives had additional tumors, including colonic polyposis. CONCLUSION We confirm the role of GCM2 germline mutations in the pathogenesis of FIHP, although at a lower rate than in the previous WES study. Further studies are needed to establish the prevalence and the role in the predisposition to FIHP of the novel variants in additional genes.

中文翻译:

家族性原发性甲状旁腺功能亢进症的完整外显子组测序。

目的家族性孤立性甲状旁腺功能亢进症(FIHP)是一种罕见的遗传性疾病,占所有原发性甲状旁腺功能亢进症(PHPT)病例的1%。它在遗传上是异质的,与包括MEN1,CDC73,CASR和最近的GCM2在内的不同基因的突变相关。该研究的目的是进一步研究意大利FIHP亲属的分子发病机理。方法我们在7个无关FIHP亲属的先证者中使用了全外显子组测序(WES)。我们在一个大家族中进行了单独的基于家族的外显子组分析,其特征是PHPT与多种与该疾病无关的肿瘤并发。还筛选了18个FIHP亲属选择的变体。家庭的临床,生化和病理学特征也进行了调查。结果在两个家族中发现了GCM2基因的三个不同变体,但只有一个(p.Tyr394Ser)已被证明具有体外致病性,并与疾病隔离。六个先证者在FAT3,PARK2,HDAC4,ITPR2和TBCE基因中携带与该疾病分离的七个杂合错义突变。在一个家庭中发现了与PHPT共分离的APC基因的遗传变异(p.Val530Ala),该家庭的受影响亲戚还有其他肿瘤,包括结肠息肉。结论我们证实了GCM2种系突变在FIHP发病机理中的作用,尽管其发生率低于以前的WES研究。需要进一步的研究来确定其他基因中新变异体的流行及其在FIHP易感性中的作用。已经显示出与病隔离的体外致病性。六个先证者在FAT3,PARK2,HDAC4,ITPR2和TBCE基因中携带与该疾病分离的七个杂合错义突变。在一个家庭中发现了与PHPT共分离的APC基因的遗传变异(p.Val530Ala),该家庭的受影响亲戚还有其他肿瘤,包括结肠息肉。结论我们证实了GCM2种系突变在FIHP发病机理中的作用,尽管其发生率低于以前的WES研究。需要进一步的研究来确定其他基因中新变异体的流行及其在FIHP易感性中的作用。已经显示出与病隔离的体外致病性。六个先证者在FAT3,PARK2,HDAC4,ITPR2和TBCE基因中携带与该疾病分离的七个杂合错义突变。在一个家庭中发现了与PHPT共分离的APC基因的遗传变异(p.Val530Ala),该家庭的受影响亲戚还有其他肿瘤,包括结肠息肉。结论我们证实了GCM2种系突变在FIHP发病机理中的作用,尽管其发生率低于以前的WES研究。需要进一步的研究来确定其他基因中新变异体的流行及其在FIHP易感性中的作用。ITPR2和TBCE基因。在一个家庭中发现了与PHPT共分离的APC基因的遗传变异(p.Val530Ala),该家庭的受影响亲戚还有其他肿瘤,包括结肠息肉。结论我们证实了GCM2种系突变在FIHP发病机理中的作用,尽管其发生率低于以前的WES研究。需要进一步的研究来确定其他基因中新变异体的流行及其在FIHP易感性中的作用。ITPR2和TBCE基因。在一个家庭中发现了与PHPT共分离的APC基因的遗传变异(p.Val530Ala),该家庭的受影响亲戚还有其他肿瘤,包括结肠息肉。结论我们证实了GCM2种系突变在FIHP发病机理中的作用,尽管其发生率低于以前的WES研究。需要进一步的研究来确定其他基因中新变异体的流行及其在FIHP易感性中的作用。
更新日期:2020-01-21
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