Association of medullary sponge kidney disease and multiple endocrine neoplasia type IIA due to RET gene mutation: is there a causal relationship?
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Adult↗
Biomedical subjects
A Calender
Publications and source records attributed to A Calender.
Molecular genetics of neuroendocrine tumors.
Through insights into the molecular genetics of neuroendocrine tumors (NETs), the genes predisposing to multiple endocrine neoplasia (MEN) syndromes were identified. In MEN1, tumors occur in the parathyroids, endocrine pancreas, anterior pituitary, adrenal glands and thymic neuroendocrine tissues. The MEN1 gene encodes a putative growth-suppressor protein, menin, binding JunD, a transcriptional factor belonging to the AP-1 complex. However, new partners binding menin remain to be found. The MEN1 gene might be involved in 1-50% of sporadic NETs. Another critical mechanism involved in NETs is the deregulation of the RET-signalling pathways by oncogenic point mutations responsible for MEN2 syndromes. MEN2 refers to the inherited forms of medullary thyroid carcinoma. The RET proto-oncogene, a tyrosine-kinase receptor, is activated by missense mutations occurring either in the extracellular dimerization domain or intracellular tyrosine kinase catalytic regions. In both cases the receptor is constitutionally activated in the absence of natural ligands. Endocrine tumors also belong to the clinical pattern of Recklinghausen (NF1) and von Hippel-Lindau (VHL) diseases. The genes for both syndromes have been characterized and provide new pathways for endocrine tumorigenesis related to G-protein physiology (NF1) and transcriptional regulation and/or endothelial cell proliferation (VHL), respectively. Here, we propose a basic overview of recent data on genetic events leading a normal endocrine cell towards a fully malignant phenotype.
Cell Transformation, Neoplastic↗
Report of the Sixth International Workshop on Human Chromosome 11 Mapping 1998. Nice, France, May 2-5, 1998.
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Animals↗
A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma.
Familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia type 2A syndromes are dominantly inherited diseases caused by activating germline mutations of the RET protooncogene. The majority of these patients carry a germline point mutation affecting one of five cysteine residues encoded by exon 10 (codon 609, 611, 618, or 620) or 11 (codon 634). In a few FMTC families, point mutations involving noncysteine codons in exon 13 (codons 768, 790, and 791), 14 (codon 804), or 15 (codon 891) have been reported. Hirschsprung's disease is a nonneoplastic disorder associated with RET mutations leading to a loss of function effect. Mutations are identified in 50% of the familial cases and are scattered along the gene. We now report the study of a FMTC family with four affected members and a history of fatal neonatal intestinal obstruction in the sister of the proband. Genetic analysis demonstrated the absence of an usual FMTC mutation and the presence of a germline 9-bp duplication in RET exon 8 in the heterozygous state in all patients with MTC. This new mutation creates an additional cysteine residue in the extracellular cysteine-rich domain of RET. Further studies are warranted to confirm whether this new mutation is causing MTC only or could be associated with Hirschsprung's disease.
Adult↗
Characterization of the mouse Men1 gene and its expression during development.
The gene responsible for multiple endocrine neoplasia type 1 (MEN1), a heritable predisposition to endocrine tumours in man, has recently been identified. Here we have characterized the murine homologue with regard to cDNA sequence, genomic structure, expression pattern and chromosomal localisation. The murine Men1 gene spans approximately 6.7 kb of genomic DNA and is comprised of 10 exons with similar genomic structure to the human locus. It was mapped to the pericentromeric region of mouse chromosome 19, which is conserved with the human 11q13 band where MEN1 is located. The predicted protein is 611 amino acids in length and overall is 97% homologous to the human orthologue. The 45 reported MEN1 mutations which alter or delete a single amino acid in human all occur at conserved residues, thereby supporting their functional significance. Two transcripts of approximately 3.2 and 2.8 kb were detected in both embryonal and adult murine tissues, resulting from alternative splicing of intron 1. By RNA in situ hybridization and Northern analysis the spatiotemporal expression pattern of Men1 was determined during mouse development. Men1 gene activity was detected already at gestational day 7. At embryonic day 14 expression was generally high throughout the embryo, while at day 17 the thymus, skeletal muscle, and CNS showed the strongest signal. In selected tissues from postnatal mouse Men1 was detected in all tissues analysed and was expressed at high levels in cerebral cortex, hippocampus, testis, and thymus. In brain the menin protein was detected mainly in nerve cell nuclei, whereas in testis it appeared perinuclear in spermatogonia. These results show that Men1 expression is not confined to organs affected in MEN1, suggesting that Men1 has a significant function in many different cell types including the CNS and testis.
Amino Acid Sequence↗
A putative human zinc-finger gene (ZFPL1) on 11q13, highly conserved in the mouse and expressed in exocrine pancreas. The European Consortium on MEN 1.
In the process of identification of the multiple endocrine neoplasia type 1 gene, which was recently published, we isolated a novel gene in the 11q13 region. This gene (named ZFPL1, for zinc-finger protein-like 1) is expressed strongly in the exocrine pancreas as a 1.4-kb polyadenylated RNA encoding a putative protein of 310 amino acids. A mouse EST contig predicts an equally sized murine protein with 91% amino acid sequence identity to the human protein. No significant homology with known proteins could be found through database screening. However, zinc-finger-like domains and leucine-zipper-like motifs in the predicted ZFPL1 protein were identified, suggesting the presence of DNA-binding and dimerization domains possibly involved in transcription regulation. This notion is supported by the presence of a putative bipartite nuclear localization signal. This paper presents the full-length cDNA sequence for this gene, its genomic structure and chromosomal orientation, and expression studies by Northern blot hybridization and RNA in situ hybridization.
Amino Acid Sequence↗
Expression and chromosomal localization of the Requiem gene.
Apoptosis in murine myeloid cell lines requires the expression of the Requiem gene, which encodes a putative zinc finger protein. We detected the protein in both cytoplasmic and nuclear subcellular fractions of murine myeloid cells and human K562 leukemia cells, which suggests that the protein might have a function distinct from a transcription factor. This distribution did not alter upon apoptosis induction by IL-3 deprivation. As an approach to investigate its role in development, we determined the spatio-temporal expression pattern in the mouse. Expression was detected in various tissues in earlier gestational age; however, confined to testes, spleen, thymus, and part of the hippocampus in the adult mouse. The expression profile is consistent with a functional role during rapid growth and cell turnover, and in agreement with a regulatory function for hematopoietic cells. The human cDNA clone sequenced showed high homology to its murine counterpart and extended the open reading frame by 20 codons upstream. The gene is located in the proximal region of mouse Chromosome (Chr) 19. In the homologous human region at 11q13, it is located at about 150 kb centromeric from MLK3.
Amino Acid Sequence↗
Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.
Amino Acid Substitution↗
Thymic carcinoids in multiple endocrine neoplasia type 1.
OBJECTIVE: To study the clinical, pathologic, and genetic features of thymic carcinoids in the setting of multiple endocrine neoplasia type 1 (MEN1) and to study means for detection and prevention of this tumor in patients with MEN1. SUMMARY BACKGROUND DATA: Thymic carcinoid is a rare malignancy, with approximately 150 cases reported to date. It may be associated with MEN1 and carries a poor prognosis, with no effective treatment. Its underlying etiology is unknown. METHODS: Ten patients with MEN1 from eight families with anterior mediastinal tumors were included in a case series study at tertiary referring hospitals. Clinicopathologic studies were done on these patients, with a review of the literature. Mutation analysis was performed on the MEN1 gene in families with clusterings of the tumor to look for genotype-phenotype correlation. Loss of heterozygosity was studied in seven cases to look for genetic abnormalities. RESULTS: Histologic studies of all tumors were consistent with the diagnosis of thymic carcinoid. Clustering of this tumor was found in some of the families-three pairs of brothers and three families with first- or second-degree relatives who had thymic carcinoid. All patients described here were men, with a mean age at detection of 44 years (range 31 to 66). Most of the patients had chest pain or were asymptomatic; none had Cushing's or carcinoid syndrome. All tumors were detected by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest. The results of octreoscans performed in three patients were all positive. Histopathologic studies were consistent with the diagnosis of thymic carcinoid and did not stain for ACTH. Mutation analysis of the families with clustering revealed mutations in different exons/introns of the MEN1 gene. Loss of heterozygosity (LOH) studies of seven tumors did not show LOH in the MEN1 region, but two tumors showed LOH in the 1p region. CONCLUSIONS: MEN1-related thymic carcinoids constitute approximately 25% of all cases of thymic carcinoids. In patients with MEN1, this is an insidious tumor not associated with Cushing's or carcinoid syndrome. Local invasion, recurrence, and distant metastasis are common, with no known effective treatment. We propose that CT or MRI of the chest, as well as octreoscanning, should be considered as part of clinical screening in patients with MEN1. We also propose performing prophylactic thymectomy during subtotal or total parathyroidectomy on patients with MEN1 to reduce the risks of thymic carcinoid and recurrence of hyperparathyroidism. Its male predominance, the absence of LOH in the MEN1 region, clustering in close relatives, and the presence of different MEN1 mutations in these families suggest the involvement of modifying genes in addition to the MEN1 gene. A putative tumor suppressor gene in 1p may be involved.
Adult↗
[Clinicogenetic study of MEN1: recent physiopathological data and clinical applications. Study Group of Multiple Endocrine Neoplasia (GENEM)].
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.
Humans↗
[Thymic and bronchial neuroendocrine tumors in multiple endocrine neoplasia type 1. GENEM1].
OBJECTIVES: Multiple endocrine neoplasia type 1 (MEN 1) mainly affects parathyroid glands, pancreatic islets and pituitary gland. The aim of this study in 95 MEN 1 patients was to examine less frequent localizations thymic and bronchic neuroendocrine tumors (NET). PATIENTS AND METHODS: Two cases of bronchic NET were observed, both in women, and 4 cases of thymic NET, all in men, giving a prevalence of 7.3%. These NET were often asymptomatic. A metastatic diffusion was observed in 3 cases. Elevated plasma levels of glycoprotein hormone alpha subunit (SU) and FSH were observed in 3 and 1 cases respectively. Immunohistochemistry indicated the tumor cells to be frequently positively stained for HCG alpha and FSH. DISCUSSION: We conclude that all patients with MEN 1 should undergo screening for thoracic NET, especially in high risk familial subgroups and in case of elevated plasma alpha SU or FSH.
Adult↗
Construction of a 1.2-Mb sequence-ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid, pancreatic, and anterior pituitary tumors. The MEN1 locus has been previously localized to chromosome 11q13, and a 2-Mb gene-rich region flanked by D11S1883 and D11S449 has been defined. We have pursued studies to facilitate identification of the MEN1 gene by narrowing this critical region to a 900-kb interval between the VRF and D11S1783 loci through melotic mapping. This was achieved by investigating 17 cosmids for microsatellite polymorphisms, which defined two novel polymorphisms at the VRF and A0138 loci, and utilizing these to characterize recombinants in MEN1 families. In addition, we have established a 1200-kb sequence-ready contig consisting of 26 cosmids, eight BACs, and eight PACs that encompass this region. The precise locations for 19 genes and three ESTs within this contig have been determined, and three gene clusters consisting of a centromeric group (VRF, FKBP2, PNG, and PLCB3), a middle group (PYGM, ZFM1, SCG1, SCG2 (which proved to be the MEN1 gene), and PPP2R5B), and a telomeric group (H4B, ANG3, ANG2, ANG1, FON, FAU, NOF, NON, and D11S2196E) were observed. These results represent a valuable transcriptional map of chromosome 11q13 that will help in the search for disease genes in this region.
Chromosome Mapping↗
Mapping of the gene encoding the B56 beta subunit of protein phosphatase 2A (PPP2R5B) to a 0.5-Mb region of chromosome 11q13 and its exclusion as a candidate gene for multiple endocrine neoplasia type 1 (MEN1).
The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localised to 11q13 by combined tumour deletion mapping and recombination studies, and a 0.5-Mb region, flanked by PYGM and D11S449, has been defined. In the course of constructing a conting, we have identified the location of the gene encoding the B56 beta subunit of protein phosphatase 2A (PP2A), which is involved in cell signal transduction pathways and thus represents a candidate gene for MEN1. We have searched for mutations in the PP2A-B56 beta coding region, together with the 5' and 3' untranslated regions in six MEN1 patients. DNA sequence abnormalities were not identified and thus the PP2A-B56 beta gene is excluded as the candidate gene for MEN1. However, our precise localisation of PP2A-B56 beta to this region of 11q13 may help in elucidating the basis for other disease genes mapping to this generich region.
Chromosome Mapping↗
Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary that represents one of the familial cancer syndromes. The MEN1 locus has been previously localised to chromosome 11q13, and a <300 kb gene-rich region flanked centromerically by PYGM and telomerically by D11S1783 defined by combined meiotic and tumour deletion mapping studies. Two candidate genes, ZFM1 and PPP2R5B, from this region have been previously excluded, and in order to identify additional candidate genes we used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes that we identified, SCG2, proved to be identical to the recently published MEN1 gene, which is likely to be a tumour suppressor gene. The SCG2 transcript was 2.9 kb in all tissues with an additional 4.2 kb transcript also being present in the pancreas and thymus. Mutational analysis of SCG2 in 10 unrelated MEN1 families identified one polymorphism and nine different heterozygous mutations (one missense, four non-sense, one insertional and three deletional frameshifts) that segregated with the disease, hence providing an independent confirmation for the identification of the MEN1 gene.
Animals↗
Genetic testing in presymptomatic diagnosis of multiple endocrine neoplasia.
Multiple endocrine neoplasias (MEN) are familial diseases characterized by endocrine neoplasms and transmitted in an autosomal dominant manner. In MEN type 1, the major lesions affect parathyroid glands, pancreatic islet cells and anterior pituitary. The MEN-1 gene has been mapped to chromosome 11q13 and a set of DNA-polymorphic markers localized close to this region provides a useful tool for presymptomatic diagnosis in MEN-1 families. MEN type 2 refers to the inherited forms of medullary thyroid carcinoma (MTC) associated or not with pheochromocytoma and hyperparathyroidism. In MEN-2, germinal mutations of the C-RET proto-oncogene which is localized on chromosome 10q11 have been found in the three clinical and allelic forms of the syndrome respectively, MEN-2 type A, B and familial isolated MTC. Mutations of C-RET are found in more than 90% of MEN-2 patients and genetic screening leads to accurate risk evaluation in families and consequently a preventive treatment of MTC and adrenal neoplasms. Recent discoveries on MEN syndromes and related familial endocrine disorders have a major clinical impact and allow a better understanding of the physiological pathways involved in familial as well as in sporadic endocrine tumor pathogenesis.
Chromosomes, Human, Pair 10↗
A large multiple endocrine neoplasia type 1 family with clinical expression suggestive of anticipation.
We describe a large multigenerational multiple endocrine neoplasia Type 1 (MEN1) family with clinical expression suggestive of anticipation. In the second and third generations, two deceased obligate gene carriers died at the ages of 85 and 76 without the history of MEN1, whereas two other living gene carriers above the age of 65 have had no clinical evidence of MEN1 to date. In the fourth generation, eight members were affected, with four having severe MEN1-related and atypical malignancies: a case of metastatic endocrine pancreatic tumor, two cases of metastatic thymic carcinoids, and a case of spinal ependymoma. In the fifth generation, all five patients were below the age of 22 when the disease was detected. MEN1 was confirmed in the family by linkage analysis using MEN1-linked microsatellite markers and by identification of a nonsense mutation in the MEN1/menin gene. Alleotyping showed loss of heterozygosity (LOH) involving the wild-type alleles in seven tumors in the family including the ependymoma, which is the first MEN1-related case that shows genetic abnormality in chromosome 11q13, suggesting that MEN1 gene might be involved in the tumorigenesis of a subset of ependymomas. In relation to clinical anticipation, repeated expansion studies were carried out but failed to detect any expansion. We conclude that this is a unique MEN1 family and that an unknown genetic mechanism might be contributing to the anticipation phenomenon. We demonstrate in this family that all gene carriers, including the very young members, will need close and careful follow-up.
Adult↗
[Recent data on molecular genetics of neuroendocrine tumors].
Genetic studies of neuroendocrine tumors were mainly performed on the basis of major syndromes predisposing to endocrine and associated proliferative lesions. Carcinoid tumors and tumors of the pancreatic islet cells occur in Multiple Endocrine Neoplasia type 1, Neurofibromatosis type I, Von Hippel-Lindau disease, Tuberous Sclerosis, suggesting that alterations of the major genes responsible for these genetic syndromes are crucial mechanisms in the neuroendocrine pathogenesis. Tumoral progression and metastasis result from secondary genetic events or deregulation involving specific genes, oncogenes, suppressor genes, and growth factors. Mechanisms involving mitosis, cell cycle, and cellular adhesion might be relevant in the metastatic process. This report is an overview of experimental data on this topic and attempt to understand the major events inducing a malignant evolution of the normal neuroendocrine tissue.
Animals↗
[Identification of the gene associated with type 1 multiple endocrine neoplasia (NEM 1) susceptibility: a new pathway in the pathogenesis of neuro-endocrine tumors].
Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder characterized by tumors of the parathyroids, endocrine pancreas, anterior pituitary, thymic, bronchic and digestive neuro-endocrine tissues and adrenal glands. The MEN1 gene has been recently cloned by two independent groups. The function of the protein encoded by the MEN1 gene is unknown until now. Germline mutations associated to the diseases in MEN1 families are distributed throughout all the open reading frame, suggesting the absence of founder effect. No consistent genotype-phenotype correlations have been yet recognized. Further studies on the functional domains of the MEN1 encoded protein could be useful to relate clinical expression of the disease with each type of mutation.
Chromosomes, Human, Pair 11↗