Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene.
Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene.
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DOI：
10.1371/journal.pone.0082292
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Guarnieri V
中科院分区：
文献类型：
--
作者：
Pazienza V;la Torre A;Baorda F;Alfarano M;Chetta M;Muscarella LA;Battista C;Copetti M;Kotzot D;Kapelari K;Al-Abdulrazzaq D;Perlman K;Sochett E;Cole DE;Pellegrini F;Canaff L;Hendy GN;D'Agruma L;Zelante L;Carella M;Scillitani A;Guarnieri V
甲状旁腺功能亢进颌肿瘤综合征（HPT-JT）的特征是原发性甲状旁腺功能亢进（PHPT）、上颌骨/下颌骨骨化性纤维瘤和15%的甲状旁腺癌。肿瘤抑制基因CDC 73/HRPT 2的失活突变已在HPT-JT患者中发现，也是散发性甲状旁腺癌/非典型腺瘤的遗传决定因素，在家族性PHPT中，也是典型腺瘤的遗传决定因素。在这里，我们报告的遗传和分子分析的CDC 73/HRPT 2基因在PHPT的影响，由于非典型和典型的甲状旁腺腺瘤，在一个案件属于家族性PHPT。在HEK 293细胞中瞬时转染Flag-taged WT和突变体CDC 73/HRPT 2蛋白，并进行功能测定，以研究变体对全蛋白表达、核定位和细胞过度生长诱导的影响。我们发现了四个CDC 73/HRPT 2基因突变，三个种系突变（c.679_680delAG、p.Val85_Val86del和p.Glu81_Pro84del），一个体细胞突变（p.Arg77Pro）。在三种情况下，突变位于核仁定位信号（NoLS）内。三种NoLS变体导致相应突变蛋白质或mRNA或两者的不稳定性。当在HEK 293细胞中转染时，NoLS突变的蛋白质错误定位为细胞质或核质-细胞质定位，最后，它们导致过度生长，与内源性蛋白质存在下的显性负干扰效应一致。
Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.
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影响因子：
9.7
作者：
Scintu, Marina;Vitale, Rita;Parrella, Paola
通讯作者：
Parrella, Paola
影响因子：
3.9
作者：
Panicker, Leelamma M.;Zhang, Jian-Hua;Simonds, William F.
通讯作者：
Simonds, William F.
影响因子：
3.5
作者：
Hahn, Michael A.;Marsh, Deborah J.
通讯作者：
Marsh, Deborah J.
影响因子：
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作者：
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通讯作者：
Thakker, RV
影响因子：
14.8
作者：
Kelley, Lawrence A.;Sternberg, Michael J. E.
通讯作者：
Sternberg, Michael J. E.