A carregar...
Publicação
Diagnóstico molecular de formas familiares de hipercalcémia
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 2.78 MB | Adobe PDF | |||
| 10.39 KB | Internal XML |
Autores
Orientador(es)
Resumo(s)
A hipersecreção de parathormona (PTH), associada a hipercalcémia, constitui uma endocrinopatia designada por hiperparatiroidismo primário (HPT), que pode resultar da hiperactividade de adenomas (80-85%), hiperplasia (15-20%) ou carcinomas (cerca de 1%) das paratiróides. O hiperparatiroidismo surge com maior frequência na forma esporádica, no entanto, cerca de 10% dos doentes apresentam uma forma familiar. Na presente tese, pretendeu-se identificar e caracterizar mutações germinais nos genes CaSR, HRPT2 e MEN1, envolvidos em formas familiares de hipercalcémia, respectivamente, hipercalcémia e hipocalciúria familiar (FHH)/hiperparatiroidismo neonatal severo (NSHPT), hiperparatiroidismo e tumores nos maxilares (HPT-JT) e neoplasias endócrinas múltiplas de tipo 1 (MEN1). Foram estudados dez casos índex e dezanove familiares destes mesmos casos. A sequenciação do gene CaSR, revelou duas novas mutações (Arg69His e c.1945delG) e uma mutação já descrita na literatura (Arg680His), em duas famílias e num caso sem história familiar, com FHH/NSHPT. Em dois casos com tumores das paratiróides, sem história familiar da doença, foram identificadas duas novas mutações germinais no gene HRPT2 (Arg76stop e c.518del4bp), sugerindo que as lesões apresentadas por estes indivíduos representavam uma expressão incompleta da síndrome HPT-JT. A detecção de uma mutação somática (Leu5Pro) no gene HRPT2, num carcinoma da paratiróide de uma doente portadora de uma mutação germinal neste gene, confirmou a inactivação total e a função oncosupressora do gene HRPT2. Estudos de segregação com marcadores de microssatélites, em dois novos indivíduos de uma família previamente estudada, em que tinha sido detectada uma extensa delecção germinal no gene MEN1, del (exão 7 região 3' não traduzida), revelaram que estes indivíduos não tinham herdado o haplotipo associado ao alelo mutado. O estudo desenvolvido neste trabalho permitiu não só a identificação precoce de dez portadores de mutações germinais em genes envolvidos na hipercalcémia familiar, mas também uma melhor compreensão dos mecanismos moleculares envolvidos na tumorigénese das paratiróides
The hypersecretion of parathormone (PTH), associated to hypercalcemia, is an endocrinopathy designated as primary hyperparathyroidism (HPT), which may result from the hyperactivity of adenomas (80-85%), hyperplasia (15-20%) or carcinomas (about 1 %) of the parathyroid glands. Primary hyperparathyroidism usually occurs sporadically, however, approximately 10% of the patients present a familial form. The aim of the present study was to identify and characterize germ line mutations in the CaSR, HRPT2 and MEN1 genes, which are involved in familial forms of hypercalcemia, respectively, familial hypocalciuric hypercalcemia (FHH)/neonatal severe hyperparathyroidism (NSHPT), hyperparathyroidism-jaw tumour (HPT-JT), and multiple endocrine neoplasia type 1 (MEN1). Ten probands and nineteen relatives were studied. Sequencing analysis of the CaSR gene revealed two novel mutations (Arg69His and c.1945delG) and one previously described (Arg680His), in two families and one case with no family history, with FHH/NSHPT. In two cases presenting parathyroid tumours, with no family history of the disease, two novel germ line mutations in the HRPT2 gene (Arg76stop and c.518del4bp) were identified, suggesting that the parathyroid lesions represented an incomplete expression of HPT-JT syndrome. The detection of a somatic HRPT2 mutation (Leu5Pro) in the parathyroid carcinoma of a patient carrying a germ line mutation in this gene, confirmed the total inactivation and the oncosupression function of the HRPT2 gene. Segregation studies, using microsatellites markers, in two new individuals, from a previously studied family with a large deletion in the MEN1 gene, del (exon 7 3' non translated region), revealed that these individuals did not have inherited the haplotype associated to the mutant allele. The study developed in the present thesis, allowed the early identification of ten individuals carrying germ line mutations in genes involved in familial hypercalcemia and contributed to a better understanding of molecular mechanisms involved in parathyroid tumorigenesis
The hypersecretion of parathormone (PTH), associated to hypercalcemia, is an endocrinopathy designated as primary hyperparathyroidism (HPT), which may result from the hyperactivity of adenomas (80-85%), hyperplasia (15-20%) or carcinomas (about 1 %) of the parathyroid glands. Primary hyperparathyroidism usually occurs sporadically, however, approximately 10% of the patients present a familial form. The aim of the present study was to identify and characterize germ line mutations in the CaSR, HRPT2 and MEN1 genes, which are involved in familial forms of hypercalcemia, respectively, familial hypocalciuric hypercalcemia (FHH)/neonatal severe hyperparathyroidism (NSHPT), hyperparathyroidism-jaw tumour (HPT-JT), and multiple endocrine neoplasia type 1 (MEN1). Ten probands and nineteen relatives were studied. Sequencing analysis of the CaSR gene revealed two novel mutations (Arg69His and c.1945delG) and one previously described (Arg680His), in two families and one case with no family history, with FHH/NSHPT. In two cases presenting parathyroid tumours, with no family history of the disease, two novel germ line mutations in the HRPT2 gene (Arg76stop and c.518del4bp) were identified, suggesting that the parathyroid lesions represented an incomplete expression of HPT-JT syndrome. The detection of a somatic HRPT2 mutation (Leu5Pro) in the parathyroid carcinoma of a patient carrying a germ line mutation in this gene, confirmed the total inactivation and the oncosupression function of the HRPT2 gene. Segregation studies, using microsatellites markers, in two new individuals, from a previously studied family with a large deletion in the MEN1 gene, del (exon 7 3' non translated region), revealed that these individuals did not have inherited the haplotype associated to the mutant allele. The study developed in the present thesis, allowed the early identification of ten individuals carrying germ line mutations in genes involved in familial hypercalcemia and contributed to a better understanding of molecular mechanisms involved in parathyroid tumorigenesis
Descrição
Tese de mestrado, Biologia (Biologia Molecular e Genética), 2008, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Biologia molecular Hipercalcémia Teses de mestrado