Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors.
The hyperparathyroidism-jaw tumor (HPT-JT) syndrome is an autosomal dominant disorder characterized by the occurrence of parathyroid tumors in association with ossifying fibromas of the maxilla and/or mandible. The gene responsible for HPT-JT, known as CDC73, was identified in 2002 and encodes a 531 amino acid protein known as parafibromin. Parafibromin is predominantly a nuclear protein that interacts directly with beta-catenin and also forms part of the RNA polymerase associated factor-1 complex (Paf1C) that regulates transcription. Heterozygous germline CDC73 mutations are detected in the majority of patients with HPT-JT, and the demonstration of loss of heterozygosity (LOH) at the CDC73 locus in tumors from affected individuals is consistent with a tumor suppressor role. Somatic CDC73 mutations are a frequent finding in nonfamilial (i.e., sporadic) parathyroid carcinomas and have also been reported in benign sporadic parathyroid tumors as well as sporadic renal and fibro-osseous jaw tumors. To date, 111 independent CDC73 mutations have been identified (68 germline; 38 somatic; 5 undefined), and these occur throughout the coding region and splice sites of the CDC73 gene, with the majority (>80%) predicting premature truncation of the parafibromin protein. These CDC73 mutations, together with their clinical and biological relevance, are reviewed.
Newey
Paul J
PJ
Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
Bowl
Michael R
MR
Cranston
Treena
T
Thakker
Rajesh V
RV
D000595:Amino Acid Sequence; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics* / Q000473:pathology; D008334:Mandible / Q000473:pathology; D008437:Maxilla / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D012319:RNA Polymerase II / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
C454900:CDC73 protein, human; D009687:Nuclear Proteins; C501972:PAF1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D012319:RNA Polymerase II