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.
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.
Authors: J D Carpten; C M Robbins; A Villablanca; L Forsberg; S Presciuttini; J Bailey-Wilson; W F Simonds; E M Gillanders; A M Kennedy; J D Chen; S K Agarwal; R Sood; M P Jones; T Y Moses; C Haven; D Petillo; P D Leotlela; B Harding; D Cameron; A A Pannett; A Höög; H Heath; L A James-Newton; B Robinson; R J Zarbo; B M Cavaco; W Wassif; N D Perrier; I B Rosen; U Kristoffersson; P D Turnpenny; L-O Farnebo; G M Besser; C E Jackson; H Morreau; J M Trent; R V Thakker; S J Marx; B T Teh; C Larsson; M R Hobbs Journal: Nat Genet Date: 2002-11-18 Impact factor: 38.330
Authors: K J Bradley; M R Hobbs; I D Buley; J D Carpten; B M Cavaco; J E Fares; P Laidler; S Manek; C M Robbins; I S Salti; N W Thompson; C E Jackson; R V Thakker Journal: J Intern Med Date: 2005-01 Impact factor: 8.989
Authors: Orit Rozenblatt-Rosen; Takashi Nagaike; Joshua M Francis; Syuzo Kaneko; Karen A Glatt; Christina M Hughes; Thomas LaFramboise; James L Manley; Matthew Meyerson Journal: Proc Natl Acad Sci U S A Date: 2009-01-09 Impact factor: 11.205
Authors: Jessica Costa-Guda; Chetanya Pandya; Maya Strahl; Patricia Taik; Robert Sebra; Rong Chen; Andrew V Uzilov; Andrew Arnold Journal: J Endocr Soc Date: 2021-05-08