Identification and Functional Characterization of Three NoLS (Nucleolar Localisation Signals) Mutations of the CDC73 Gene

• DOI: 10.1371/journal.pone.0082292
• Publication Date: 2013-12-05T21:53:17Z
• Authors: Valerio Pazienza; Annamaria la Torre; Filomena Baorda; Michela Alfarano; Massimiliano Chetta; Lucia Anna Muscar...; Claudia Battista; Massimiliano Copetti; Dieter Kotzot; Klaus Kapelari; Dalia Al-Abdulrazzaq; Kusiel Perlman; Etienne Sochett; David E. C. Cole; Fabio Pellegrini; Lucie Canaff; Geoffrey N. Hendy; Leonardo D’Agruma; Leopoldo Zelante; Massimo Carella; Alfredo Scillitani; Vito Guarnieri
• Keywords: Parathyroid carcinoma

Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and parathyroid carcinoma in 15% of cases. Inactivating mutations the tumour suppressor CDC73/HRPT2 gene have been found HPT-JT patients also as genetic determinants sporadic carcinoma/atypical adenomas and, rarely, typical adenomas, familial PHPT. Here we report molecular analysis three affected PHPT due to atypical one case belonging Flag-tagged WT mutant proteins were transiently transfected HEK293 cells functional assays performed order investigate effect variants on whole protein expression, nuclear localization cell overgrowth induction. We identified four mutations, germline (c.679_680delAG, p.Val85_Val86del p.Glu81_Pro84del), somatic (p.Arg77Pro). In cases mutation was located within Nucleolar Localisation Signals (NoLS). The NoLS led instability either corresponding mutated or mRNA both. When cells, mislocalized with a predeliction for cytoplasmic nucleo-cytoplasmic finally, they resulted overgrowth, consistent dominant negative interfering presence endogenous protein.