Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene.
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...
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doaj-aac17d3fe7c84c75bc8f76fec6a213b42020-11-25T01:55:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01812e8229210.1371/journal.pone.0082292Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene.Valerio PazienzaAnnamaria la TorreFilomena BaordaMichela AlfaranoMassimiliano ChettaLucia Anna MuscarellaClaudia BattistaMassimiliano CopettiDieter KotzotKlaus KapelariDalia Al-AbdulrazzaqKusiel PerlmanEtienne SochettDavid E C ColeFabio PellegriniLucie CanaffGeoffrey N HendyLeonardo D'AgrumaLeopoldo ZelanteMassimo CarellaAlfredo ScillitaniVito GuarnieriHyperparathyroidism 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.http://europepmc.org/articles/PMC3855386?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Valerio Pazienza Annamaria la Torre Filomena Baorda Michela Alfarano Massimiliano Chetta Lucia Anna Muscarella 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 |
spellingShingle |
Valerio Pazienza Annamaria la Torre Filomena Baorda Michela Alfarano Massimiliano Chetta Lucia Anna Muscarella 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 Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. PLoS ONE |
author_facet |
Valerio Pazienza Annamaria la Torre Filomena Baorda Michela Alfarano Massimiliano Chetta Lucia Anna Muscarella 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 |
author_sort |
Valerio Pazienza |
title |
Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. |
title_short |
Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. |
title_full |
Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. |
title_fullStr |
Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. |
title_full_unstemmed |
Identification and functional characterization of three NoLS (nucleolar localisation signals) mutations of the CDC73 gene. |
title_sort |
identification and functional characterization of three nols (nucleolar localisation signals) mutations of the cdc73 gene. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC3855386?pdf=render |
work_keys_str_mv |
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