Identification and Functional Characterization of Three NoLS Nucleolar Localisation Signals Mutations of the CDC73 GeneReportar como inadecuado




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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.



Autor: Valerio Pazienza , Annamaria la Torre , Filomena Baorda, Michela Alfarano, Massimiliano Chetta, Lucia Anna Muscarella, Claudia Ba

Fuente: http://plos.srce.hr/



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