The Experts below are selected from a list of 3108 Experts worldwide ranked by ideXlab platform
Deborah J Marsh - One of the best experts on this subject based on the ideXlab platform.
-
the Tumor suppressor cdc73 interacts with the ring finger proteins rnf20 and rnf40 and is required for the maintenance of histone 2b monoubiquitination
Human Molecular Genetics, 2012Co-Authors: Michael A Hahn, Anthony J Gill, Adele Clarkson, Kristieann Dickson, Stuart Jackson, Deborah J MarshAbstract:Monoubiquitination of histone H2B is a dynamic post-translational histone modification associated with transcriptional elongation and the DNA damage response. To date, dysregulation of histone monoubiquitination has not been linked to pathogenic mutations in genes encoding proteins, or co-factors, catalyzing this modification. The Tumor suppressor cell division cycle 73 (CDC73) is mutated and/or down-regulated in parathyroid carcinoma, renal, breast, gastric and colorectal Tumors, as well as in the germline of patients with the familial disorder-hyperparathyroidism Jaw Tumor syndrome. Using CDC73 as bait in a yeast two-hybrid assay, we identified the ring finger proteins RNF20 and RNF40 as binding partners of this Tumor suppressor. These polypeptides constitute a heterodimeric complex that functions as the E3 ubiquitin ligase for monoubiquitination of histone H2B at lysine 120 (H2B-K120). We show that RNF20 and RNF40 bind to discrete, but closely located, residues on CDC73. Monoubiquitinated H2B-K120 was significantly reduced after loss of nuclear CDC73, both in vitro upon down-regulation of CDC73, and in CDC73 mutant parathyroid Tumors. A second histone modification, trimethylation of histone 3 at lysine 4 (H3-K4me3), remained unchanged in the presence of mutant or down-regulated CDC73, suggesting that H3-K4me3 is not always tightly linked to H2B-K120 monoubiquitination for transcription as previously described. This is the first report of pathogenic mutations affecting histone monoubiquitination. We conclude that CDC73 is required for the maintenance of H2B-K120 monoubiquitination and propose that reduction in levels of monoubiquitinated H2B-K120 is a major mechanism whereby mutations in CDC73 exert their Tumorigenic effect.
-
accuracy of combined protein gene product 9 5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma
The Journal of Clinical Endocrinology and Metabolism, 2009Co-Authors: Viive M Howell, Anthony J Gill, Adele Clarkson, Oliver Gimm, Anne E Nelson, Robert Dunne, Leigh Delbridge, Bruce G Robinson, Deborah J MarshAbstract:Context: Parafibromin, encoded by HRPT2, is the first marker with significant benefit in the diagnosis of parathyroid carcinoma. However, because parafibromin is only involved in up to 70% of parathyroid carcinomas and loss of parafibromin immunoreactivity may not be observed in all cases of HRPT2 mutation, a complementary marker is needed. Objective: We sought to determine the efficacy of increased expression of protein gene product 9.5 (PGP9.5), encoded by ubiquitin carboxyl-terminal esterase L1 (UCHL1) as an additional marker to loss of parafibromin immunoreactivity for the diagnosis of parathyroid carcinoma. Design: In total, 146 parathyroid Tumors and nine normal tissues were analyzed for the expression of parafibromin and PGP9.5 by immunohistochemistry and for UCHL1 by quantitative RT-PCR. These samples included six hyperparathyroidism-Jaw Tumor syndrome-related Tumors and 24 sporadic carcinomas. Results: In Tumors with evidence of malignancy, strong staining for PGP9.5 had a sensitivity of 78% for ...
-
loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism Jaw Tumor hpt jt syndrome related adenomas from sporadic parathyroid adenomas and hyperplasias
The American Journal of Surgical Pathology, 2006Co-Authors: Anthony J Gill, Adele Clarkson, Oliver Gimm, Juliane Keil, Henning Dralle, Viive M Howell, Deborah J MarshAbstract:Parathyroid carcinoma is notoriously difficult to diagnose with confidence in borderline cases. Commonly there is a long lag time between diagnosis and clinical evidence of malignant behavior even in histopathologically straightforward lesions. There is therefore a need for a novel adjunctive marker to assist in the diagnosis of carcinoma. Parafibromin is the protein encoded by the putative Tumor suppressor gene HRPT2. Mutations predicted to inactivate parafibromin were first detected in the germline of patients with hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome. Subsequently, somatic mutations have been identified in the majority of sporadic carcinomas. We performed immunohistochemistry for parafibromin on 115 parathyroid tissues comprising 4 HPT-JT-related Tumors (3 adenomas and 1 carcinoma), 11 sporadic parathyroid carcinomas, 79 sporadic adenomas, 3 multiple endocrine neoplasia 2A-related adenomas, 2 sporadic primary hyperplasias, 2 multiple endocrine neoplasia (MEN)-1-related hyperplasias, 6 secondary hyperplasias, 4 tertiary hyperplasias, and 4 normal parathyroid glands. There was complete absence of nuclear staining in 3 of 4 (75%) HPT-JT-related Tumors and 8 of 11 (73%) sporadic parathyroid carcinomas and focal weak staining in 1 of 4 HPT-JT Tumors and 2 of 11 sporadic parathyroid carcinomas. Only 1 parathyroid carcinoma exhibited diffuse strong nuclear expression of parafibromin. In contrast, 98 of 100 non-HPT-JT-related benign parathyroids showed diffuse strong nuclear positivity and 2 of 100 showed weak positive staining. We conclude that, in the correct clinical and pathologic context, complete absence of nuclear staining for parafibromin is diagnostic of parathyroid carcinoma or an HPT-JT-related Tumor.
-
identification of a functional bipartite nuclear localization signal in the Tumor suppressor parafibromin
Oncogene, 2005Co-Authors: Michael A Hahn, Deborah J MarshAbstract:Parafibromin is a putative Tumor suppressor encoded by HRPT2, mutations in which have been implicated in the familial Tumor syndrome hyperparathyroidism Jaw Tumor syndrome (HPT-JT), and sporadic parathyroid carcinoma. Recently, parafibromin has been shown to be an accessory factor for RNA polymerase II as part of the human Paf1 complex, suggesting, as has been shown for its yeast homologue (Cdc73), that it may have a role as an important regulator of transcription. Parafibromin has also been shown to interact with a histone methyltransferase complex that methylates histone H3 and to inhibit proliferation when overexpressed in mammalian cell lines. Despite these findings, the cellular localization of parafibromin has been controversial, with reports of both nuclear and nucleocytoplasmic localization. We have expressed wild-type and mutant parafibromin tagged with enhanced green fluorescent protein and have identified a functional bipartite nuclear localization signal (NLS) at residues 125–139 (nucleotides 373–417), KRAADEVLAEAKKPR, that is evolutionarily conserved and critical for the nuclear localization of parafibromin. We have also shown that the C-terminal arm of this bipartite NLS plays the primary role in nuclear localization. In support of these findings, specific HRPT2 mutations identified in HPT-JT or sporadic parathyroid carcinoma predicted to truncate parafibromin upstream of or within this NLS disrupt nuclear localization.
William F. Simonds - One of the best experts on this subject based on the ideXlab platform.
-
the parafibromin Tumor suppressor protein inhibits cell proliferation by repression of the c myc proto oncogene
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Ling Lin, Jianhua Zhang, Leelamma M Panicker, William F. SimondsAbstract:Parafibromin is a Tumor suppressor protein encoded by HRPT2, a gene recently implicated in the hereditary hyperparathyroidism–Jaw Tumor syndrome, parathyroid cancer, and a subset of kindreds with familial isolated hyperparathyroidism. Human parafibromin binds to RNA polymerase II as part of a PAF1 transcriptional regulatory complex. The physiologic targets of parafibromin and the mechanism by which its loss of function can lead to neoplastic transformation are poorly understood. We show here that RNA interference with the expression of parafibromin or Paf1 stimulates cell proliferation and increases levels of the c-myc proto-oncogene product, a DNA-binding protein and established regulator of cell growth. This effect results from both c-myc protein stabilization and activation of the c-myc promoter, without alleviation of the c-myc transcriptional pause. Chromatin immunoprecipitation demonstrates the occupancy of the c-myc promoter by parafibromin and other PAF1 complex subunits in native cells. Knockdown of c-myc blocks the proliferative effect of RNA interference with parafibromin or Paf1 expression. These experiments provide a previously uncharacterized mechanism for the anti-proliferative action of the parafibromin Tumor suppressor protein resulting from PAF1 complex-mediated inhibition of the c-myc proto-oncogene.
-
The parafibromin Tumor suppressor protein interacts with actin-binding proteins actinin-2 and actinin-3
Molecular cancer, 2008Co-Authors: Sunita K. Agarwal, William F. Simonds, Stephen J. MarxAbstract:Germline and somatic inactivating mutations in the HRPT2 gene occur in the inherited hyperparathyroidism-Jaw Tumor syndrome, in some cases of parathyroid cancer and in some cases of familial hyperparathyroidism. HRPT2 encodes parafibromin. To identify parafibromin interacting proteins we used the yeast two-hybrid system for screening a heart cDNA library with parafibromin as the bait. Fourteen parafibromin interaction positive preys representing 10 independent clones encoding actinin-2 were isolated. Parafibromin interacted with muscle alpha-actinins (actinin-2 and actinin-3), but not with non-muscle alpha-actinins (actinin-1 and actinin-4). The parafibromin-actinin interaction was verified by yeast two-hybrid, GST pull-down, and co-immunoprecipitation. Yeast two-hybrid analysis revealed that the N-terminal region of parafibromin interacted with actinins. In actin sedimentation assays parafibromin did not dissociate skeletal muscle actinins from actin filaments, but interestingly, parafibromin could also bundle/cross-link actin filaments. Parafibromin was predominantly nuclear in undifferentiated proliferating myoblasts (C2C12 cells), but in differentiated C2C12 myotubes parafibromin co-localized with actinins in the cytoplasmic compartment. These data support a possible contribution of parafibromin outside the nucleus through its interaction with actinins and actin bundling/cross-linking. These data also suggest that actinins (and actin) participate in sequestering parafibromin in the cytoplasmic compartment.
-
parafibromin product of the hyperparathyroidism Jaw Tumor syndrome gene hrpt2 regulates cyclin d1 prad1 expression
Oncogene, 2005Co-Authors: Geoffrey E Woodard, Sunita K. Agarwal, Stephen J. Marx, Jianhua Zhang, Ling Lin, William F. SimondsAbstract:Parafibromin is the 531-amino-acid protein product encoded by HRPT2, a putative Tumor suppressor gene recently implicated in the autosomal dominant hyperparathyroidism-Jaw Tumor familial cancer syndrome, sporadic parathyroid cancer, and a minority of families with isolated hyperparathyroidism. Parafibromin contains no identified functional domains but bears sequence homology to Cdc73p, a budding yeast protein component of the RNA polymerase II-associated Paf1 complex. This study addressed the expression and functional properties of human parafibromin. A survey of human and mouse tissues analysed with polyclonal antibodies to parafibromin showed specific immunoreactivity in adrenal and parathyroid glands, kidney, heart, and skeletal muscle. Subcellular fractionation and laser confocal microscopy of normal human parathyroid gland demonstrated expression of parafibromin in both the cytoplasmic and nuclear compartments. Parafibromin was expressed in four parathyroid adenomas but was absent from two parathyroid carcinomas. Transient overexpression of wild-type parafibromin, but not its Leu64Pro missense mutant implicated in parathyroid cancer and familial isolated hyperparathyroidism, inhibited cell proliferation, and blocked expression of cyclin D1, a key cell cycle regulator previously implicated in parathyroid neoplasia. These results demonstrate that human parafibromin is a nucleocytoplasmic protein with functions consistent with its postulated role as a Tumor suppressor protein.
-
hrpt2 encoding parafibromin is mutated in hyperparathyroidism Jaw Tumor syndrome
Nature Genetics, 2002Co-Authors: John D. Carpten, William F. Simonds, A. Villablanca, Christiane M. Robbins, Lars Forsberg, Silvano Presciuttini, Joan E Baileywilson, Elizabeth M Gillanders, A M Kennedy, Jindong ChenAbstract:We report here the identification of a gene associated with the hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a Tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a Tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid Tumors.
Rajesh V Thakker - One of the best experts on this subject based on the ideXlab platform.
-
multiple endocrine neoplasia type 1 men1 phenocopy due to a cell cycle division 73 cdc73 variant
Journal of the Endocrine Society, 2020Co-Authors: Kate E Lines, Lisa B Nachtigall, Laura E Dichtel, Treena Cranston, Hannah Boon, Xun Zhang, Kreepa Kooblall, Mark Stevenson, Rajesh V ThakkerAbstract:Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid Tumors, pituitary adenomas, and pancreatic neuroendocrine neoplasms (PNENs). MEN1 is caused by germline MEN1 mutations in > 75% of patients, and the remaining 25% of patients may have mutations in unidentified genes or represent phenocopies with mutations in genes such as cell cycle division 73 (CDC73), the calcium sensing receptor (CASR), and cyclin-dependent kinase inhibitor 1B (CDKN1B), which are associated with the hyperparathyroidism-Jaw Tumor syndrome, familial hypocalciuric hypercalcemia type 1, and MEN4, respectively. Here, we report a heterozygous c.1138C>T (p.Leu380Phe) CDC73 germline variant in a clinically diagnosed MEN1 patient, based on combined occurrence of primary hyperparathyroidism, acromegaly, and a PNEN. Characterization of the PNEN confirmed it was a neuroendocrine neoplasm as it immuno-stained positively for chromogranin and glucagon. The rare variant p.Leu380Phe occurred in a highly conserved residue, and further analysis using RNA-Scope indicated that it was associated with a significant reduction in CDC73 expression in the PNEN. Previously, CDC73 mutations have been reported to be associated with Tumors of the parathyroids, kidneys, uterus, and exocrine pancreas. Thus, our report of a patient with PNEN and somatotrophinoma who had a CDC73 variant, provides further evidence that CDC73 variants may result in a MEN1 phenocopy.
-
cdc73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Eeva Korpihyovalti, Rajesh V Thakker, Treena Cranston, Eeva Ryhanen, Johanna Arola, Kristiina Aittomaki, Timo Sane, Camilla SchalinjanttiAbstract:Context: CDC73 mutations frequently underlie the hyperparathyroidism-Jaw Tumor syndrome, familial isolated hyperparathyroidism (FIHP), and parathyroid carcinoma. It has also been suggested that CDC73 deletion analysis should be performed in those patients without CDC73 mutations. Objective: To investigate for CDC73 deletion in a family with FIHP previously reported not to have CDC73 mutations. Patients and Methods: Eleven members (six affected with primary hyperparathyroidism and five unaffected) were ascertained from the family, and multiplex ligation-dependent probe amplification was performed to detect CDC73 deletion using leukocyte DNA. Results: A previously unreported deletion of CDC73 involving exons 1–10 was detected in five affected members and two unaffected members who were 26 and 39 years of age. Two affected members had parathyroid carcinomas at the ages of 18 and 32 years, and they had Ki-67 proliferation indices of 5 and 14.5% and did not express parafibromin, encoded by CDC73. Primary hyper...
-
role of multiple endocrine neoplasia type 1 mutational analysis in clinical practice
Endocrine Practice, 2011Co-Authors: Paul J Newey, Rajesh V ThakkerAbstract:ABSTRACT Objective: To review and assess the role of MEN1 mutational analysis in clinical practice. Methods: Articles relevant to MEN1 mutation testing and screening were reviewed. Results: Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder characterized by the combined occurrence of Tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary gland. MEN 1 is associated with premature mortality attributable primarily to malignant pancreatic neuroendocrine Tumors and fore-gut carcinoids. The MEN1 gene is located on chromosome 11q13, and germline MEN1 mutations are highly penetrant and lead to Tumor development in > 99% of patients by the age of 45 years. Current consensus guidelines recommend an integrated program of mutational analysis of the MEN1 gene and a combination of biochemical and radiologic screening to detect the early development of Tumors and thereby reduce the morbidity and mortality associated with MEN 1. Our results reveal that MEN1 mutational analysis helps to confirm the clinical diagnosis, identify asymptomatic family members who have a MEN1 mutation and require screening from an early age, and identify the 50% of family members who do not have the MEN1 mutation and can therefore have the burden of screening and anxiety regarding potential disease removed. Moreover, MEN1 mutational analysis helps to resolve diagnostic challenges due to phenocopies, which occur in 5% to 10% of families with MEN 1. Conclusion: MEN1 mutational analysis facilitates clinical management and provides benefits to patients and families with MEN 1. (Endocr Pract 2011;17[Suppl 3]: 8-17) Abbreviations: HPT-JT = hyperparathyroidism-Jaw Tumor; MEN 1 = multiple endocrine neoplasia type 1; NETs = neuroen-docrine Tumors
-
cell division cycle protein 73 homolog cdc73 mutations in the hyperparathyroidism Jaw Tumor syndrome hpt jt and parathyroid Tumors
Human Mutation, 2010Co-Authors: Paul J Newey, Treena Cranston, Michael R Bowl, Rajesh V ThakkerAbstract: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 β-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. Hum Mutat 31:295–307, 2010. © 2010 Wiley-Liss, Inc.
-
Hereditary hyperparathyroidism-Jaw Tumor syndrome: The endocrine Tumor gene HRPT2 maps to chromosome 1q21-q31
American Journal of Human Genetics, 1995Co-Authors: Jozsef Szabo, Brett Heath, Richard J. Zarbo, Shern L Chew, Gordon M. Besser, Virginia M Hill, Lawrence E. Mallette, Rajesh V Thakker, Charles E. Jackson, Vicki D HuffAbstract:The syndrome of hereditary hyperparathyroidism and Jaw Tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous Tumors of the mandible and/or maxilla, Wilms Tumor, and parathyroid carcinoma. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine Tumor gene designated “HRPT2.” We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genomewide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions (θ), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at θ = .0 with marker D1S212, or >106 odds in favor of linkage. In six hereditary Wilms Tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores −15.6 [D1S191] and −17.8 [D1S196], θ = .001). Nine parathyroid adenomas and one Wilms Tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms Tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine Tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms Tumor syndrome.
Bin Tean Teh - One of the best experts on this subject based on the ideXlab platform.
-
hrpt2 gene alterations in ossifying fibroma of the Jaws
Oral Oncology, 2006Co-Authors: Flavio Juliano Pimenta, Bin Tean Teh, Leticia Ferreira Gontijo Silveira, Gabriela C Tavares, Andreza Campos Silva, Paolla Freitas Perdigao, Wagner Henriques De Castro, Marcus Vinicius Gomez, Luiz De Marco, Ricardo Santiago GomezAbstract:Ossifying fibroma (OF) is a benign neoplasm related to bone characterized by a progressive enlargement of the affected Jaw. Recently, the candidate Tumor suppressor gene HRPT2 was identified and alterations in this gene were related with the Hyperparathyroidism-Jaw Tumor syndrome that is characterized by parathyroid adenoma or carcinoma, fibro-osseous lesions (mainly OF) of the Jaws, and renal lesions. The purpose of the present study was to evaluate the HRPT2 gene in OF. Tumour and blood samples were obtained from 3 patients with OF and one with juvenile ossifying fibroma (JOF). The results demonstrated three novel mutations in two out of three genotyped OF's. Interestingly, one of these patients showed a germ-line mutation after blood analysis. RT-PCR amplification was performed to analyze HRPT2 mRNA expression and only wild-type HRPT2 transcript was found in all tumours. Investigation of the parafibromin protein by immunohistochemistry showed a similar pattern of immunolocalization with strong nuclear and cytoplasmic staining in all cases. In conclusion, the present study shows for the first time mutations of HRPT2 gene in OF and suggests that OF may arise due to haploinsufficiency of the HRPT2 gene.
-
autosomal dominant primary hyperparathyroidism and Jaw Tumor syndrome associated with renal hamartomas and cystic kidney disease linkage to 1q21 q32 and loss of the wild type allele in renal hamartomas
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Bin Tean Teh, Hunter Heath, Filip Farnebo, U Kristoffersson, B Sundelin, John Cardinal, R Axelson, Alpha S Yap, M Epstein, D CameronAbstract:Hereditary hyperparathyroidism-Jaw Tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endo...
-
autosomal dominant primary hyperparathyroidism and Jaw Tumor syndrome associated with renal hamartomas and cystic kidney disease linkage to 1q21 q32 and loss of the wild type allele in renal hamartomas
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Bin Tean Teh, Hunter Heath, Filip Farnebo, U Kristoffersson, B Sundelin, John Cardinal, R Axelson, Alpha S Yap, M Epstein, D CameronAbstract:Hereditary hyperparathyroidism-Jaw Tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a Jaw Tumor and a parathyroid Tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a Tumor suppressor gene in this region.
D Cameron - One of the best experts on this subject based on the ideXlab platform.
-
autosomal dominant primary hyperparathyroidism and Jaw Tumor syndrome associated with renal hamartomas and cystic kidney disease linkage to 1q21 q32 and loss of the wild type allele in renal hamartomas
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Bin Tean Teh, Hunter Heath, Filip Farnebo, U Kristoffersson, B Sundelin, John Cardinal, R Axelson, Alpha S Yap, M Epstein, D CameronAbstract:Hereditary hyperparathyroidism-Jaw Tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endo...
-
autosomal dominant primary hyperparathyroidism and Jaw Tumor syndrome associated with renal hamartomas and cystic kidney disease linkage to 1q21 q32 and loss of the wild type allele in renal hamartomas
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Bin Tean Teh, Hunter Heath, Filip Farnebo, U Kristoffersson, B Sundelin, John Cardinal, R Axelson, Alpha S Yap, M Epstein, D CameronAbstract:Hereditary hyperparathyroidism-Jaw Tumor syndrome (HPT-JT) is an autosomal dominant disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or cystic kidney disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polycystic kidney disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a Jaw Tumor and a parathyroid Tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a Tumor suppressor gene in this region.