Abstract
Purpose: The CDC73 gene, encoding parafibromin, has been identified as a tumour suppressor gene both in hyperparathyroidism-jaw tumour (HPT-JT) syndrome and in sporadic parathyroid carcinoma. While the vast majority of CDC73 mutations affect the N-terminus or the central core of the encoded protein, as yet few mutations have been reported affecting the C-terminus. Here, we report a case (Caucasian female, 28 years) with an invasive ossifying fibroma of the left mandible and hyperparathyroidism (sCa∈=∈16 mg/dl, PTH∈=∈660 pg/mL) due to a parathyroid lesion of 20 mm, hystologically diagnosed as carcinoma. Methods: The whole CDC73 gene was screened for the presence of mutations by Sanger sequencing. Immunohistochemistry, in vitro functional assays, Western blotting, MTT assays and in-silico modelling were performed to assess the effect of the detected mutation. Results: Sequence analysis of the CDC73 gene in the proband revealed the presence of a novel deletion affecting the C-terminus of the encoded protein (c.1379delT/p. L460Lfs*18). Clinical and genetic analyses of the available relatives led to the identification of three additional carriers, one of whom was also affected by a parathyroid lesion. Immunohistochemistry, Western blotting, MTT and in-silico modelling assays revealed that the deletion leads to down-regulation of the mutated protein, most likely through a proteasome-mediated pathway. We also found that the deletion may cause a conformational change in the C-terminus of the protein, possibly affecting its interaction with partner proteins. Finally, we found that the mutant protein enhances cellular growth. Conclusions: We report a novel mutation in the CDC73 gene that may underlie HPT-JT syndrome. This mutation appears to affect the C-terminal moiety of the encoded protein, which is thought to interact with other protein partners. The identification of these partners may be instrumental for our understanding of the CDC73-associated phenotype.
| Original language | English |
|---|---|
| Pages (from-to) | 281-288 |
| Number of pages | 8 |
| Journal | Cellular Oncology |
| Volume | 37 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- CDC73
- HPT-JT
- Hyperparathyroidism with jaw tumours
- Parafibromin
ASJC Scopus subject areas
- Cancer Research
- Molecular Medicine
- Oncology
- Medicine(all)
Cite this
A novel CDC73 gene mutation in an Italian family with hyperparathyroidism- jaw tumour (HPT-JT) syndrome. / Chiofalo, M. G.; Sparaneo, A.; Chetta, M.; Franco, R.; Baorda, F.; Cinque, L.; Granatiero, M.; D'Agruma, L.; Pezzullo, L.; Scillitani, A.; Guarnieri, V.
In: Cellular Oncology, Vol. 37, No. 4, 2014, p. 281-288.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel CDC73 gene mutation in an Italian family with hyperparathyroidism- jaw tumour (HPT-JT) syndrome
AU - Chiofalo, M. G.
AU - Sparaneo, A.
AU - Chetta, M.
AU - Franco, R.
AU - Baorda, F.
AU - Cinque, L.
AU - Granatiero, M.
AU - D'Agruma, L.
AU - Pezzullo, L.
AU - Scillitani, A.
AU - Guarnieri, V.
PY - 2014
Y1 - 2014
N2 - Purpose: The CDC73 gene, encoding parafibromin, has been identified as a tumour suppressor gene both in hyperparathyroidism-jaw tumour (HPT-JT) syndrome and in sporadic parathyroid carcinoma. While the vast majority of CDC73 mutations affect the N-terminus or the central core of the encoded protein, as yet few mutations have been reported affecting the C-terminus. Here, we report a case (Caucasian female, 28 years) with an invasive ossifying fibroma of the left mandible and hyperparathyroidism (sCa∈=∈16 mg/dl, PTH∈=∈660 pg/mL) due to a parathyroid lesion of 20 mm, hystologically diagnosed as carcinoma. Methods: The whole CDC73 gene was screened for the presence of mutations by Sanger sequencing. Immunohistochemistry, in vitro functional assays, Western blotting, MTT assays and in-silico modelling were performed to assess the effect of the detected mutation. Results: Sequence analysis of the CDC73 gene in the proband revealed the presence of a novel deletion affecting the C-terminus of the encoded protein (c.1379delT/p. L460Lfs*18). Clinical and genetic analyses of the available relatives led to the identification of three additional carriers, one of whom was also affected by a parathyroid lesion. Immunohistochemistry, Western blotting, MTT and in-silico modelling assays revealed that the deletion leads to down-regulation of the mutated protein, most likely through a proteasome-mediated pathway. We also found that the deletion may cause a conformational change in the C-terminus of the protein, possibly affecting its interaction with partner proteins. Finally, we found that the mutant protein enhances cellular growth. Conclusions: We report a novel mutation in the CDC73 gene that may underlie HPT-JT syndrome. This mutation appears to affect the C-terminal moiety of the encoded protein, which is thought to interact with other protein partners. The identification of these partners may be instrumental for our understanding of the CDC73-associated phenotype.
AB - Purpose: The CDC73 gene, encoding parafibromin, has been identified as a tumour suppressor gene both in hyperparathyroidism-jaw tumour (HPT-JT) syndrome and in sporadic parathyroid carcinoma. While the vast majority of CDC73 mutations affect the N-terminus or the central core of the encoded protein, as yet few mutations have been reported affecting the C-terminus. Here, we report a case (Caucasian female, 28 years) with an invasive ossifying fibroma of the left mandible and hyperparathyroidism (sCa∈=∈16 mg/dl, PTH∈=∈660 pg/mL) due to a parathyroid lesion of 20 mm, hystologically diagnosed as carcinoma. Methods: The whole CDC73 gene was screened for the presence of mutations by Sanger sequencing. Immunohistochemistry, in vitro functional assays, Western blotting, MTT assays and in-silico modelling were performed to assess the effect of the detected mutation. Results: Sequence analysis of the CDC73 gene in the proband revealed the presence of a novel deletion affecting the C-terminus of the encoded protein (c.1379delT/p. L460Lfs*18). Clinical and genetic analyses of the available relatives led to the identification of three additional carriers, one of whom was also affected by a parathyroid lesion. Immunohistochemistry, Western blotting, MTT and in-silico modelling assays revealed that the deletion leads to down-regulation of the mutated protein, most likely through a proteasome-mediated pathway. We also found that the deletion may cause a conformational change in the C-terminus of the protein, possibly affecting its interaction with partner proteins. Finally, we found that the mutant protein enhances cellular growth. Conclusions: We report a novel mutation in the CDC73 gene that may underlie HPT-JT syndrome. This mutation appears to affect the C-terminal moiety of the encoded protein, which is thought to interact with other protein partners. The identification of these partners may be instrumental for our understanding of the CDC73-associated phenotype.
KW - CDC73
KW - HPT-JT
KW - Hyperparathyroidism with jaw tumours
KW - Parafibromin
UR - http://www.scopus.com/inward/record.url?scp=84906935573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906935573&partnerID=8YFLogxK
U2 - 10.1007/s13402-014-0187-3
DO - 10.1007/s13402-014-0187-3
M3 - Article
VL - 37
SP - 281
EP - 288
JO - Cellular oncology (Dordrecht)
JF - Cellular oncology (Dordrecht)
SN - 2211-3428
IS - 4
ER -