Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene

PloS One
Valerio PazienzaVito Guarnieri

Abstract

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 H...Continue Reading

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Citations

Aug 13, 2014·Cellular Oncology (Dordrecht)·M G ChiofaloV Guarnieri
Oct 10, 2015·Langenbeck's Archives of Surgery·Maurizio IacoboneMenno Vriens
Sep 8, 2017·Human Mutation·Luís CardosoRajesh V Thakker
Sep 25, 2017·The Journal of Clinical Endocrinology and Metabolism·Luigia CinquePaolo Prontera
Jan 14, 2020·International Journal of Endocrinology·Francesca Torresan, Maurizio Iacobone
Jun 24, 2021·Journal of the Endocrine Society·Jessica Costa-GudaAndrew Arnold

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Methods Mentioned

BETA
PCR
Polymerase Chain
transfection

Software Mentioned

Phyre2 , Protein Homology Fold RecognitionEngine ,
ChemDraw
SAS
ImageJ

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