Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0221002 (primary hyperparathyroidism)
 4,921 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germ-line mutations of the MEN1 gene were analyzed in five cases of familial and four cases of sporadic multiple endocrine neoplasia type 1 (MEN-1), six cases in three independent pedigrees of familial pituitary adenoma without MEN-1, and three cases of familial isolated primary hyperparathyroidism (FIHP) in Japanese. Eight different types of germ-line mutations in all nine cases of MEN-1 were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all nine tumors of these cases with microsatellite analysis. No germ-line mutation of the MEN1 gene was detected in three pedigrees of familial pituitary adenoma and three cases of FIHP. LOH on 11q13 was detected in two cases in one pedigree of familial pituitary adenoma, and one of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in three cases of FIHP. Based on these, we conclude that the loss of function of menin is etiological for familial or sporadic MEN-1, but not for FIHP or most familial pituitary adenoma without MEN-1.
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PMID:Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese. 970 85

Biochemical signs and severity of symptoms of primary hyperparathyroidism (pHPT) differ among patients, and little is known of any coupling of clinical characteristics of nonfamilial pHPT to genetic abnormalities in the parathyroid tumors. Mutations in the recently identified MEN1 gene at chromosome 11q13 have been found in parathyroid tumors of nonfamilial pHPT. Using microsatellite analysis for loss of heterozygosity (LOH) at 11q13 and DNA sequencing of coding exons, the MEN1 gene was studied in 49 parathyroid lesions of patients with divergent symptoms, operative findings, histopathological diagnosis, and biochemical signs of nonfamilial pHPT. Allelic loss at 11q13 was detected in 13 tumors, and 6 of them demonstrated previously unrecognized somatic missense and frameshift deletion mutations of the MEN1 gene. Many of the detected mutations would most likely result in a nonfunctional menin protein, consistent with a tumor suppressor mechanism. Clinical and biochemical characteristics of HPT were apparently unrelated to the presence or absence of LOH and the MEN1 gene mutations. However, the demonstration of LOH at 11q13 and MEN1 gene mutations in small parathyroid adenomas of patients with slight hypercalcemia and normal serum PTH levels suggest that altered MEN1 gene function may also be important for the development of mild sporadic pHPT.
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PMID:Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. 970 20

Multiple Endocrine Neoplasia type 1 (MEN1, OMIM 131100, Wermer syndrome) is characterized by inherited predisposition to primary hyperparathyroidism, endocrine pancreatic-duodenal, pituitary, adrenal glands tumors and benign and/or malignant proliferations of diffuse neuroendocrine tumors in thymus and bronchi, formerly defined as carcinoid tumors. Minor lesions have been observed in MEN1 patients such as cutaneous tumors (angiofibroma, lipoma, lentiginosis), thyroid epithelioma and tumors of the central nervous system, mainly spinal ependymoma. The MEN1 gene, a locus encompassing a 9 kb of genomic sequence contains 10 exons, the first exon being untranslated. The protein encoded by this gene was called menin and has been shown to contain two nuclear localization signals (NLS), suggesting a major function in the nucleus. Germline MEN1 mutations have been described in more than 150 families and are spread throughout the entire coding sequence. More than 70% of the mutations alter one or both NLS and no genotype-phenotype correlations were found to date. The MEN1 gene seems to be involved in a 20-30% of sporadic parathyroid and pancreatic/bronchic neuroendocrine tumors, but less than 1% of pituitary sporadic tumors. Further knowledge on the intracellular function of menin will be needed to understand the pathogenic effect of truncating and missense mutations of this gene in the initiation of endocrine cells tumorigenesis.
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PMID:[Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)]. 1018 86

We report here our genetic findings of a family in which 14 members were affected with isolated primary hyperparathyroidism. Hyperparathyroidism is the main feature of multiple endocrine neoplasia type 1 (MEN1), making the recently cloned MEN1 gene a prime candidate gene in this family. Significantly positive lod scores were achieved with D11S4946 (3.36) and D11S4940 (3.53), and by combining the results from these two markers, a maximum positive lod score of 4.12 at recombination fraction 0.00 was obtained. Mutation analysis of MEN1 performed by full sequencing identified a missense mutation in exon 4, causing an amino acid change from glutamine to proline at codon 260. This mutation (Q260P) was present in all affected family members, and the inheritance of the mutation was in complete agreement with the disease-associated haplotype. In comparison with the recent functional studies of the menin protein interactions, this mutation is located in a region with little or no binding activity to JunD and activating protein-1 transcription factor. We conclude that some of the familial isolated primary hyperparathyroidism families constitute a milder variant of MEN 1, which is associated with a functionally milder missense mutation.
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PMID:Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. 1063 81

The multiple endocrine neoplasia type 1 (MEN1) gene seems to be a tumor suppressor that encodes a 610-amino acid protein termed menin and that plays an important role in the development of MEN1 syndrome. Recent reports indicate that heterozygous germline mutations of this gene are responsible for the disease onset of MEN1. In this study we examined the expression of menin in parathyroid tumors from primary hyperparathyroidism (PHP), secondary hyperparathyroidism (SHP), and MEN1 and thyroid tumors including Basedow's disease, thyroid cancer, and adrenocortical tumors. Both ribonucleic acid and protein from these tumors were applied to RT-PCR and Western blotting, respectively. Primers for RT-PCR were designed to amplify the sequence between exons 2 and 3 of the MEN1 gene. Specific antibody against menin was generated in guinea pigs immunized with the recombinant peptide from amino acid residues 443-535 of menin made by using glutathione-S-transferase (GST) gene fusion. Menin messenger ribonucleic acid was strongly expressed on RT-PCR analysis in the parathyroid tumors from both PHP and SHP. Western blotting revealed a specific band of approximately 67 kDa in parathyroid tumors from PHP and SHP, with a much weaker such band detected in thyroid tumors. Menin expression was down-regulated in MEN1 samples, including nonsense mutation and deletion mutant. These findings suggest that menin is predominantly synthesized and stored in parathyroid tumors resulting from PHP and SHP.
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PMID:Expression of menin in parathyroid tumors. 1090 16

The multiple endocrine neoplasia syndromes are divided into two categories: MEN type I and MEN type II. The MEN type II syndrome is further divided into MEN IIa and MEN IIb. The syndromes are characterized by benign and malignant changes in two or more endocrine organs, as well as incidental changes in nervous, muscular and connective tissue. Two main forms can be distinguished: the MEN-I syndrome with hyperplasia of the parathyroid gland, accompanied by islet cell tumor and pituitary adenoma; the MEN-II syndrome with medullary thyroid carcinoma in combination with bilateral pheochromocytoma and hyperplasia of the parathyroid gland (MEN IIa), while type IIb is characterized by the additional appearance of neurocutaneous manifestations without primary hyperparathyroidism. Characteristics shared by these syndromes include the involved cell type, most of the tumors are composed of one or more specific polypeptide- and biogenic amine-producing cell types (APUD--amine precursor uptake and decarboxylation). The second characteristic is the increased incidence in certain families. The hereditary component is autosomal dominant with variable expression but high penetrance. Mechanisms of tumorigenesis differ in these syndromes. While MEN I is caused by an inherited mutation of a tumor suppressor gene, menin, located on the long arm of chromosome 11, MEN II is caused by activation of the RET proto-oncogene. We have reported the case of a young man exhibiting bilateral pheochromocytoma. In addition, the patient showed mild primary hyperparathyroidism and marfanoid habitus, all these stigmata usually being part of the MEN-II syndrome. Although this described patient showed a phenotypic mixture of the MEN-IIa and MEN-IIb syndrome, the genetic analysis for MEN II and von-Hippel-Lindau gene did not reveal any pathologic mutations, the endocrine disorders described here are not related to multiple endocrine neoplasia syndromes.
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PMID:Multiple endocrine neoplasia (MEN)--an overview and case report--patient with sporadic bilateral pheochromocytoma, hyperparathyroidism and marfanoid habitus. 1120 36

Primary hyperparathyroidism is a common endocrine disease with a multifaceted genetic background, the elucidation of which has only begun. Among others, loss of the short arm of chromosome 1 and somatic inactivation of the multiple endocrine neoplasia type 1 gene (MEN1) in 11q13 represent significant alterations in the tumorigenesis. In the present study deletions of 1p were characterized and the findings were evaluated in relation to the loci of MEN1 and histone deacetylase 1 gene (HDAC1), a menin interacting partner in 1p, as well as to the clinical characteristics. Overall 1p LOH was detected in 18 of the 42 tumors analyzed (43%), and from the deletion patterns a main target interval of 40 cM was identified within 1p band 32.3-36.2. The mapping of HDAC1 centromeric of the main interval, and the lack of altered mRNA expression in tumors with LOH, suggest that HDAC1 is not the main target for 1p deletions in parathyroid tumors. Twenty-five of the 42 tumors (60%) showed alteration of either 1p, of the MEN1 locus, or both. Tumors with LOH at 11q13 had a significantly higher weight than tumors with 1p LOH. In conclusion, LOH in primary sporadic parathyroid adenomas occur frequently on the distal part of chromosome 1p and are thus clearly different from parathyroid carcinomas where the deletions are more proximally located. The findings support that the short arm of chromosome 1 harbors at least two different tumor suppressor genes involved in parathyroid tumorigenesis, the exact identification of which may provide a molecular basis for differential diagnosis of benign and malignant disease in the future.
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PMID:Distinct target regions for chromosome 1p deletions in parathyroid adenomas and carcinomas. 1223 10

Three Japanese patients (a man and his two sons) in a family with clinical diagnosis of familial multiple endocrine neoplasia type 1 (MEN1) suffered from insulinoma(s), primary hyperparathyroidism and pituitary microadenoma. Genomic DNA of the patients was analyzed by sequencing for the MEN1 gene and an insertion of six nucleotides, CTGCAG, in exon 4, resulting in insertion of two amino acids, Leu-Gln, after the 256th amino acid of the menin (256insLQ), was identified. CTGCAG is a palindromic sequence and repeated twice in the wild-type allele (nucleotides 879-890). It is speculated that mutations involving only exon 4 of the MEN1 gene might induce development of insulinoma(s).
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PMID:A novel six-nucleotide insertion in exon 4 of the MEN1 gene, 878insCTGCAG, in three patients with familial insulinoma and primary hyperparathyroidism. 1241 5

Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have investigated the roles of transforming growth factor (TGF)-beta and menin, the product of the multiple endocrine neoplasia type 1 (Men1) gene, in the proliferation and PTH production of parathyroid cells from either patients with secondary hyperparathyroidism or Men1. TGF-beta was expressed in the parathyroid endocrine cells. Addition of TGF-beta to parathyroid cells from patients with secondary hyperparathyroidism inhibited their proliferation and PTH secretion. These responses to TGF-beta were lost when menin was specifically inactivated by antisense oligonucleotides. Moreover, TGF-beta did not affect the proliferation and PTH production of parathyroid cells from a Men1 patient. These results indicate that menin is required for TGF-beta action in the parathyroid. We conclude that TGF-beta is an important autocrine/paracrine negative regulator of parathyroid cell proliferation and PTH secretion and that loss of TGF-beta signaling due to menin inactivation contributes to parathyroid tumorigenesis.
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PMID:Menin inactivation leads to loss of transforming growth factor beta inhibition of parathyroid cell proliferation and parathyroid hormone secretion. 1502 66

Primary hyperparathyroidism (PHPT) is characterized by excessive PTH secretion in respect to calcium homeostasis needs, due to parathyroid adenoma (80% of cases), hyperplasia (15-20%), or carcinoma (1-2%). In familial forms of PHPT, several mutations have an established role: menin gene for MEN type 1, RET for MEN type 2a, calcium-sensing receptor gene for familial hypocalciuric hypercalcemia, parafibromin gene for PHPT-jaw tumour and carcinoma. Etiology of sporadic adenomas (80% of PHPT cases) is less defined, being most commonly found a mutation of menin gene or activation of PRAD1 oncogene. In recent years, the classical features of the disease became less common. Typically, bone involvement is now represented by a reduced bone mass at skeletal sites more rich in cortical tissue. Prominently trabecular skeletal sites are relatively spared, because of the anabolic effects of a slight PTH excess on trabecular tissue. PHPT patients may have increased fracture risk, though it is not clear why bone damage is more severe in a subgroup of patients. Clinical features of hypercalcemia may be fatigue, anorexia, thirst, and polyuria. Vague neurological and psychiatric symptoms, such as weakness, anxiety, depression, paresthesias, and muscular cramps may ameliorate after parathyroidectomy. Recent reports indicate increased cardiovascular mortality in PHPT patients. Diagnosis is based on the detection of hypercalcemia, together with inappropriately high serum PTH levels. Preoperative localization of the diseased glands is mandatory in persistent or recurrent PHPT, as like as when minimally invasive surgery is planned. High resolution ultrasonography and SPECT double-phase 99m Tc-sestamibi scintigraphy are the most commonly employed techniques. Intraoperatory PTH assay may confirm successful surgery when serum concentrations decrease more than 50%. Surgical therapy is indicated in patients with renal or skeletal complications, such as in those with previous parathyrotoxic crisis. Many surgeons in recent years adopted minimally invasive parathyroidectomy. Medical treatment is an option for patients unwilling or unfitted for surgery because of severe concomitant diseases. Employed therapy includes estrogens, SERMs, bisphosphonates and calcimimetics.
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PMID:[Primary hyperparathyroidism]. 1638 70


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