Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome

Mizusawa, Noriko; Uchino, Shigehiko; Iwata, Takeo; Tsuyuguchi, Masaru; Suzuki, Yasuyo; Mizukoshi, Tsunenori; Yamashita, Yoshio; Sakurai, Akihiro; Suzuki, Shinichi; Beniko, Mutsuo; Tahara, Hideki; Fujisawa, Masato; Kamata, Nobuyuki; Fujisawa, Kenji; Yashiro, Tohru; Nagao, Daisuke; Golam, Hossain Md.; Sendo, Toshiaki; Noguchi, Shiro; Yoshimoto, Katsuhiko

doi:10.1111/j.1365-2265.2006.02534.x

Cited by 77 publications

(57 citation statements)

References 33 publications

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“…Most clinically significant sporadic or germline mutations of HRPT2 predict loss of parafibromin expression or function (1,5,6,(19)(20)(21)(22)(23)(24)(25), supporting the view that parafibromin is a tumor suppressor protein. The mechanism(s) by which loss of parafibromin function promotes neoplasia are nonetheless largely unknown.…”

Section: Discussionmentioning

confidence: 78%

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

Zhang²,

Panicker³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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HRPT2 ͉ hyperparathyroidism ͉ parathyroid cancer ͉ PAF1 complex T he tumor suppressor gene HRPT2 was recently identified by positional candidate cloning (1). Germline mutation of HRPT2 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome (HPT-JT), an autosomal dominant syndrome with high but incomplete penetrance (2). The major features are primary hyperparathyroidism (including 15% of all affected by HPT-JT with parathyroid cancer), jaw tumors, bilateral renal cysts, and, less commonly, solid renal tumors (2, 3). Germline inactivating HRPT2 mutation has also been reported in a minority of kindreds with familial isolated hyperparathyroidism (FIHP) (1, 4) and in up to 30% of patients with apparently sporadic parathyroid cancer (5, 6).HRPT2 encodes parafibromin, a 531 amino acid, putative tumor suppressor protein. Parafibromin demonstrates weak homology to Cdc73p, a budding yeast protein component of the RNA polymerase II-associated Paf1 complex. Recent evidence suggests that in humans, parafibromin interacts with RNA polymerase II via a human PAF1 complex whose other protein components include human Paf1, CTR9, Leo1 (7-9), and the WD40-repeat protein Ski8 (9). The molecular targets of parafibromin and the mechanism by which its inactivation can lead to neoplastic transformation are poorly understood. We show here that parafibromin, in the context of the PAF1 complex, mediates repression of the c-myc protooncogene through both transcriptional and posttranscriptional mechanisms. This finding provides a previously uncharacterized mechanism for the anti-proliferative action of parafibromin and a plausible mechanism by which its loss of function promotes neoplasia.

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Section: Discussionmentioning

confidence: 78%

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

Zhang²,

Panicker³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The majority of FIHP with MEN 1 mutations presented with mild hypercalcemia and multiglandular disease or parathyroid hyperplasia, similar to what is usually seen in MEN1 (8)(9)(10)(11)(12)(13). On the other hand, in FIHP families where HRPT2 gene mutations have been detected, the clinical presentation is more severe and in all cases the histopathological diagnosis was parathyroid carcinoma or adenoma, frequently associated with atypical or cystic features similar to those seen in HPT-JT syndrome (13)(14)(15).…”

Section: Introductionmentioning

confidence: 94%

“…On the other hand, in FIHP families where HRPT2 gene mutations have been detected, the clinical presentation is more severe and in all cases the histopathological diagnosis was parathyroid carcinoma or adenoma, frequently associated with atypical or cystic features similar to those seen in HPT-JT syndrome (13)(14)(15). These observations suggest that FIHP could be subdivided in at least two major genetic subsets: a MEN1-related FIHP, characterized by milder forms of hyperparathyroidism, typically presenting as multiglandular disease; and HRPT-related variety, characterized by an aggressive disease, parathyroid adenomas or carcinomas and HRPT2 gene mutations that could be regarded as a variant of HPT-JT syndrome.…”

Section: Introductionmentioning

confidence: 99%

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

Silveira

Dias²,

Marinho³

et al. 2008

Arq Bras Endocrinol Metab

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It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafi bromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafi bromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75%), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotypegenotype correlation in larger series, to best defi ne their treatment. RESUMO Formas Familiares de Hiperparatireoidismo Relacionadas a Mutações no Gene HRPT2: Estudos Moleculares Poderiam Direcionar Procedimentos Cirúrgicos?A melhor conduta nas formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2 ainda é controvertida. Cirurgias conservadoras, minimamente invasivas ou mais agressivas já foram propostas por diferentes grupos. Objetivamos estudar a seqüência e a expressão do gene HRPT2, além do desfecho clínico, após seguimento de até 32 anos de uma família brasileira com hiperparatireodismo familiar isolado (FIHP). Utilizamos dados clínicos e bioquímicos, seqüenciamento direto do HRPT2 além de análise da expressão da parafi bromina através da RT-PCR e imunohistoquímica. Foi identifi cada mutação nonsense no éxon 1 (c.96G>A)(p.Trp32X) em todos os membros afetados que foram estudados. A análise do mRNA transcrito, através da RT-PCR, demonstrou ausência do transcrito no tecido tumoral. A imunohistoquímica também evidenciou ausência da parafi bromina. Nessa família houve alta (75%) prevalência de recorrência ou persistência da doença após paratireoidectomia parcial o que nos levou a considerar fundamental discutir uma abordagem cirúrgica mais agressiva com os outros familiares portadores da mutação caso critérios de indicação cirúrgica sejam atingidos. Dessa maneira, até que estudos mais amplos estabeleçam uma correlação genótipo-fenótipo no hiperparatireoidismo familiar relacionado a mutações no HRPT2, a abordagem cirúrgica deverá ser individualizada. Silveira et al. HRPT2 mutations in FIHP and surgery

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“…Mutações no gene HRPT2 têm sido relacionadas ao desenvolvimento de carcinoma de paratireóide (22), sendo sugerida a necessidade de avaliação do gene HRPT2 em famílias com HFI (12), especialmente aquelas com presença de carcinoma de paratireóide, adenomas atípicos ou adenomas com alterações císticas (17,18).…”

Section: Discussão E Conclusõesunclassified

“…Mutações germinativas no gene da NEM 1, CASR e HRPT2 já foram descritas em famílias com HFI (13,17,18) e novas técnicas de screening genético têm sido desenvolvidas (19).…”

Section: Discussão E Conclusõesunclassified

Hiperparatireoidismo primário familiar isolado: análise e descrição de uma família com seis casos índices

Moulin

Cantoni

Neto

et al. 2007

Arq Bras Endocrinol Metab

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RESUMOObjetivamos descrever e analisar uma família com seis casos de hiperparatireoidismo familiar isolado (HFI), uma rara doença hereditária de padrão autossômico dominante, caracterizada por hiperparatireoidismo primário sem associação com outras doenças ou tumores endocrinológicos. O diagnóstico foi realizado através da demonstração de hipercalcemia, aumento dos níveis de paratormônio e tumores de paratireóide à histopatologia, excluindo-se neoplasias endócrinas múltiplas do tipo 1 (NEM 1) e do tipo 2a (NEM 2a), além da síndrome hiperparatireoidismo/tumor de mandíbula (HPT/TM). Analisamos a descrição dos exames diagnósticos iniciais, a abordagem cirúrgica, os laudos histopatológicos pós-operatórios e suas evoluções. A primeira paciente operada neste instituto há 20 anos, recidivou onze anos após, e possuía uma irmã com diagnóstico prévio, o que motivou a investigação de outros familiares. A observação do caráter familial nesses pacientes contribuiu para a facilitação diagnóstica e encaminhamento terapêutico dos mesmos, assim como a orientação clínica e genética à família. ABSTRACT Familial Isolated Primary Hyperparathyroidism -Description and Analyses of Six Cases.Our objective is to evaluate and describe one family with six cases of familial isolated primary hyperparathyroidism (HFI), a rare hereditable disorder with an autossomal dominant mode of inheritance. It is characterized by a primary hyperparathyroidism without association with other endocrine tumors or diseases. The HFI diagnosis relied on the demonstration of hypercalcemia, inappropriately high levels of parathyroid hormone, and parathyroid adenomas, plus exclusion of NEM 1/2a and HPT/TM syndrome in this family. We analyzed the description of the first diagnosis, surgical approach, postoperative histopathological results and their development process. The first patient, treated in our institute twenty years ago, has recidivated eleven years after the treatment. Her sister had had the same diagnosis, which motivated us to investigate theirs relatives. The analysis of the characteristics that run in these patients' family has contributed to facilitate their diagnosis and therapeutic treatment, including clinical and genetic orientation of this family.

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Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism–jaw tumour syndrome

Abstract: Our results confirm the need to test for HRPT2 in FIHP families, especially those with parathyroid carcinomas, atypical adenomas or adenomas with cystic change.

Cited by 77 publications

References 33 publications

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

Hiperparatireoidismo primário familiar isolado: análise e descrição de uma família com seis casos índices

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