Germline Multiple Endocrine Neoplasia Type 1 Mutations Research Articles

Germline CDKN1B/p27Kip1 Mutation in Multiple Endocrine Neoplasia

Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients. Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients. Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing. The study was conducted at nonprofit academic research and medical centers. Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study. We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features. A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients. Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

Characteristics of the Danish families with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations – of which 12 are novel – found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.

Thymic carcinoid in multiple endocrine neoplasia 1: genotype–phenotype correlation and prevention

Thymic carcinoid is a rare multiple endocrine neoplasia type 1 (MEN1)-associated tumour that is a major cause of death in MEN1 patients. Here, we describe a previously unreported MEN1 family in which two siblings presented with malignant thymic carcinoids. All six siblings share a novel nonsense mutation Q395X on exon 8 of the MEN1 gene. The index patient developed a thymic carcinoid despite an earlier prophylactic transcervical thymectomy, and one other sibling had an incidental malignant thymic carcinoid discovered following prophylactic thymectomy, both cases demonstrating the weakness and strength of this surgical approach. We then review the spectrum of germline MEN1 mutations associated with thymic carcinoids to evaluate the possibility of a genotype-phenotype correlation. In the 22 separate MEN1 families with thymic carcinoids, all but two (91%) have mutations coding for a truncated protein. There is clearly a high prevalence of truncating mutations in MEN1-related thymic carcinoids although when compared with the prevalence of truncating mutations in all reported MEN1 mutations, it is not statistically significant (P = 0.39). Further studies are warranted to evaluate pathways of tumorigenesis of thymic carcinoids with regard to loss of function of menin.

Expression and Functional Analysis of Menin in a Multiple Endocrine Neoplasia Type 1 (MEN1) Patient with Somatic Loss of Heterozygosity in Chromosome 11q13 and Unidentified Germline Mutation of the MEN1 Gene

In some patients with multiple endocrine neoplasia type 1 (MEN1) it is not possible to identify a germline mutation in the MEN1 gene. We sought to document the loss of expression and function of the MEN1 gene product, menin, in the tumors of such a patient. The proband is an elderly female patient with primary hyperparathyroidism, pancreatic islet tumor, and breast cancer. Her son has primary hyperparathyroidism. No germline MEN1 mutation was identified in the proband or her son. However, loss of heterozygosity at the MEN1 locus and complete lack of menin expression were demonstrated in the proband's tumor tissue. The proband's cultured parathyroid cells lacked the normal reduction in proliferation and parathyroid hormone secretion in response to transforming growth factor- beta. This assessment provided insight into the molecular pathogenesis of the patient and provides evidence for a critical requirement for menin in the antiproliferative action of transforming growth factor-beta.

Acromegaly in a multiple endocrine neoplasia type 1 (MEN1) family with low penetrance of the disease

Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome that is characterised by the occurrence of tumours in the parathyroid glands, the endocrine pancreas, the pituitary gland and the adrenal glands and by neuroendocrine carcinoid tumours, often at a young age. The penetrance of MEN1 among gene carriers is reported to be high; 82-99% at age 50. We present a patient with a history of parathyroid adenomas also showing signs of acromegaly. He turned out to be a carrier of a MEN1 germ-line mutation in intron 3 (IVS3-6C > G). This germ-line mutation was also found in nine of his family members. However, none of these relatives have developed any MEN1-related lesion yet, although several are older than 60 years. To our knowledge, a MEN1 family with as few clinical features as this family has not been reported to date. Because MEN1 patients have an increased risk of developing acromegaly, insulin-like growth factor (IGF-I) levels are monitored periodically. We investigated whether IGF-I levels might serve as a presymptomatic marker for acromegaly; 9% (3/33) of MEN1 patients showed temporary IGF-I elevations. One patient (1/3) later developed clinical signs of acromegaly. Possibly, acromegaly in MEN1 is preceded by a transient preacromegalic state.

Clinical and genetic features of patients with multiple endocrine tumors who have neither family history nor MEN1 germline mutations.

Multiple endocrine neoplasia type 1 (MEN1) is an hereditary tumor syndrome that involves specific endocrine organs such as parathyroids, anterior pituitary gland, and endocrine pancreas. The responsible gene for this syndrome, MEN1, has been isolated and that enabled genetic diagnosis for patients with endocrine tumors and early detection of asymptomatic gene carriers in affected families. Nevertheless, there are a considerable number of patients with MEN1 who have neither family history nor germline MEN1 mutations. In this article, clinical features of such patients are described. Among 53 MEN1 patients we have seen during the last 20 yr, five patients who did not have either MEN1 germline mutation or family history were categorized as MEN1 phenocopy. During the same period, we have also experienced three patients who had primary hyperparathyroidism and adrenocortical tumor but had no apparent family history of endocrine tumors. These patients were considered as MEN1 phenocopy variants and included in the study. The mean age of MEN1 phenocopy patients (including variants) at diagnosis was 48 yr, which was not significantly different from that of probands of familial MEN1 (46 yr) who carry heterozygous MEN1 gene mutations. In the majority of MEN1 phenocopy patients, primary hyperparathyroidism was due to a single parathyroid adenoma. In contrast to a previous report, we found that MEN1 phenocopy patients are not necessarily older than probands of familial MEN1. Phenotypic expression of such patients is variable, thus differentiation of familial MEN1 and MEN1 phenocopy cannot be made based on age and clinical phenotype alone.

Prevalence of multiple endocrine neoplasia type 1 in young patients with apparently sporadic primary hyperparathyroidism or pancreaticoduodenal endocrine tumours.

The appropriate treatment for a sporadic endocrine tumour may be different from those that present as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. As primary hyperparathyroidism (pHPT) and pancreaticoduodenal endocrine tumours (PETs) are the most common organ manifestations of MEN1, the prevalence of germline mutations in the MEN1 gene was determined in young patients with apparently sporadic pHPT or PETs. Eighteen of 705 patients with pHPT and 11 of 93 patients with PETs operated on between 1987 and 2001 had no family history of MEN1, only one organ manifestation and were aged 40 years or less at the time of diagnosis. Fifteen patients with pHPT and eight with PETs agreed to MEN1 gene mutation analysis, which was performed by single-strand conformational variant analysis and direct DNA sequencing. Two of 15 patients (13.3 (95 per cent confidence interval (c.i.) 1.6 to 40.4) per cent) with apparently sporadic pHPT had a MEN1 germline mutation. Both mutations were found in patients with pHPT due to multiglandular disease, whereas the remaining 13 patients had a solitary adenoma. None of the eight patients with PETs carried a MEN1 germline mutation. Sporadic pHPT due to multiglandular disease in patients younger than 40 years may represent the first organ manifestation of MEN1 despite a negative family history.

Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by a triad of neoplasia affecting the parathyroid glands, enteropancreatic endocrine tissue and the anterior pituitary gland. In order to define the prevalence of MEN1 germ-line mutations in Southern Chinese patients with MEN1 syndrome, we performed direct sequencing of the entire open reading frame of the MEN1 gene for 12 index patients and their first-degree relatives. Six patients had familial MEN1 syndrome and six had apparently sporadic disease. Nine different germ-line mutations at the MEN1 gene were identified, including three novel mutations [248-249delTT in exon 2, K559X(AAG --> TAG) in exon 10 and IVS 2nt + 2(G --> T) in intron 2]. All patients with familial MEN1 syndrome were heterozygous carriers of a germ-line mutation and MEN1-related disorders were only evident in their first-degree relatives who also carried the mutation. All patients with an enteropancreatic lesion were mutation carriers and the absence of mutation in three apparently sporadic MEN1 patients with only hyperparathyroidism and pituitary microadenoma might represent the presence of MEN1 phenocopy. The finding of MEN1 germ-line mutation in all patients with familial MEN1 syndrome suggests that genetic screening should be useful in our population to identify affected individuals within a kindred and allow early detection of MEN1-related tumours.

Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders.

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by the combined occurrence of tumours of the parathyroid glands, pancreatic islet cells and anterior pituitary gland. Mutation analysis of the MEN1 gene has enabled the genetic diagnosis of patients with MEN1. Two MEN1-related disorders - familial isolated hyperparathyroidism (FIHP) and familial pituitary adenoma - are considered to be variants of MEN1, or at least to be incompletely expressed variants. Germline mutations of the MEN1 gene have been reported in some with FIHP, but familial pituitary adenoma usually lacks the MEN1 mutation and has been described as a genetically distinct disorder. In this work, we investigated five Korean families with MEN1, one family with FIHP and one family with familial pituitary adenoma. Polymerase chain reaction (PCR)-based single-strand conformation polymorphism (PCR-SSCP) analysis, denaturing high-performance liquid chromatography (DHPLC) and sequencing were used to detect the MEN1 mutations. Screening of the genetic variations of the MEN1 gene revealed four germline mutations in five typical MEN1 families. All four germline mutations led to truncated proteins or a change in the amino acids of the functional domains. In this study, we identified three novel MEN1 germline mutations (969C >A, 973G >C and 1213C >T) and one previously reported mutation (200-201insAGCCC). The frequency of the MEN1 germline mutation in Korean MEN1 families (four of five; 80%) was similar to those reported previously. In accordance with previous studies, no MEN1 germline mutation was detected in two families with FIHP or familial pituitary adenoma.

Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by endocrine tumors of the parathyroids, the pancreatic islets, and the anterior pituitary. The MEN1 gene encodes menin, a nuclear protein interacting with JunD/AP1, Smad3, NFkappaB, and other proteins involved in transcription and cell growth regulation. Here, by exhaustive sequence analysis of 170 probands/families collected through a French clinical network, we identified 165 mutations located in coding parts of the MEN1 gene, which represent 114 distinct MEN1 germline alterations. These mutations have been included in a MEN1-locus specific database available on the world wide web together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Our mutation series included 56 frameshifts, 23 nonsense, 27 missense, and eight deletion or insertion in-frame mutations. Mutations were spread over the entire coding sequence. Taken together, most missense and in-frame MEN1 genomic alterations affect one or all domains of menin interacting with JunD [codons 1-40; 139-242; 323-428], Smad3 [distal to codon 478], and NFkappaB [codons 276-479], three major effectors in transcription and cell growth regulation. No correlation has been observed between genotype and MEN1 phenotype. We suggest that the knowledge of structure and location of a specific mutation has not been useful in clinical practice for the follow-up of affected patients and asymptomatic gene carriers. Our results provide the largest series of MEN1 mutations published to date. They will be a useful tool for further studies focusing on the functional effects of missense mutations and understanding which mechanisms or pathways related to multiple menin interactions might be involved in tumorigenesis of endocrine cells.

Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.

Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds.

10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterised by the combined occurrence of tumours of the parathyroid glands, the enteropancreatic neuroendocrine system and the anterior pituitary gland. The genetic defect has been mapped to the long arm of chromosome 11q13, and the MEN1-gene was recently identified by positional cloning. Genetic screening for MEN1 germline mutations allows the identification of gene carriers in affected kindreds. Biochemical and radiological screening for MEN1 tumours allows an earlier diagnosis and treatment, and, thus may reduce morbidity and mortality. Since there is no consensus about the frequency and the extent of the necessary screening investigations, evaluation of proposed screening programs is of importance. The aims of our study were to identify the MEN1-gene mutations and to detect the gene-carriers in 10 Swiss MEN1 families, as well as to assess biochemical and radiological screening methods. The study included 45 members from 10 MEN1 families. Every family had a different type of MEN1-gene mutation. Thirty out of 45 family members were gene mutation carriers. Twenty-two MEN1-gene carriers had typical MEN1 tumours: parathyroid, enteropancreatic and pituitary tumours were found in 21, 14 and 1 patients, respectively. Applying a defined screening program the following manifestations in asymptomatic MEN1-gene carriers were detected: 9 primary hyperparathyroidism, 3 nonfunctioning pancreatic tumours, 1 gastrinoma, 1 nonfunctioning microadenoma of the pituitary and 1 macronodular adrenal hyperplasia. The genetic screening facilitates the identification of individuals who carry MEN1-gene mutations, and allows one to exclude non-mutant gene carriers from further investigations. The prospective biochemical and radiological screening of gene mutation carriers allows the earlier detection of MEN1-associated tumours. Therefore, it might be expected that morbidity and mortality of the MEN1 could be reduced.

10 Swiss kindreds with multiple endocrine neoplasia type 1: assessment of screening methods.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease characterised by the combined occurrence of tumours of the parathyroid glands, the enteropancreatic neuroendocrine system and the anterior pituitary gland. The genetic defect has been mapped to the long arm of chromosome 11q13, and the MEN1-gene was recently identified by positional cloning. Genetic screening for MEN1 germline mutations allows the identification of gene carriers in affected kindreds. Biochemical and radiological screening for MEN1 tumours allows an earlier diagnosis and treatment, and, thus may reduce morbidity and mortality. Since there is no consensus about the frequency and the extent of the necessary screening investigations, evaluation of proposed screening programs is of importance. The aims of our study were to identify the MEN1-gene mutations and to detect the gene-carriers in 10 Swiss MEN1 families, as well as to assess biochemical and radiological screening methods. The study included 45 members from 10 MEN1 families. Every family had a different type of MEN1-gene mutation. Thirty out of 45 family members were gene mutation carriers. Twenty-two MEN1-gene carriers had typical MEN1 tumours: parathyroid, enteropancreatic and pituitary tumours were found in 21, 14 and 1 patients, respectively. Applying a defined screening program the following manifestations in asymptomatic MEN1-gene carriers were detected: 9 primary hyperparathyroidism, 3 nonfunctioning pancreatic tumours, 1 gastrinoma, 1 nonfunctioning microadenoma of the pituitary and 1 macronodular adrenal hyperplasia. The genetic screening facilitates the identification of individuals who carry MEN1-gene mutations, and allows one to exclude non-mutant gene carriers from further investigations. The prospective biochemical and radiological screening of gene mutation carriers allows the earlier detection of MEN1-associated tumours. Therefore, it might be expected that morbidity and mortality of the MEN1 could be reduced.

The MEN1 gene and associated diseases: an update.

Heterozygous germline mutations of the tumor suppressor gene MEN1 are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited familial cancer syndrome characterized by the combined occurrence of pituitary, parathyroid, and enteropancreatic tumors. Various types of mutations likely causing loss of the gene function have been identified throughout the entire gene region in patients with MEN1 and related disorders including a small fraction of familial isolated hyperparathyroidism (FIHP). Neither mutation hot spot nor phenotype-genotype correlation has been established in classical MEN1, although some missense mutations may be specifically associated with a phenotype of FIHP. Familial isolated pituitary tumor and atypical familial MEN1 consisting of only pituitary tumor and hyperparathyroidism usually lack germline MEN1 mutations, suggesting that these familial endocrine tumor syndromes are genetic entities distinct from MEN1. DNA test for MEN1 germline mutations is a robust tool for diagnosis of predisposition to MEN1, and will be useful for the counseling and management of patients and their families. In this review, we will summarize the most recent findings on the MEN1 gene, focusing primarily on germline mutations and associated diseases.

Discovery of germline and somatic mutations in apparently sporadic parathyroid tumours

Abstract Background To discriminate between sporadic and hereditary parathyroid tumours and characterize multiple endocrine neoplasia type 1 (MEN1) somatic mutations, MEN1 gene mutations were examined in patients with apparently sporadic parathyroid tumours. Methods DNA was extracted from fresh frozen parathyroid tumour specimens from 112 patients, as well as from peripheral blood leucocytes (PBL) from 60 of the 112 patients. Sequencing was performed to examine exons 2–10 of the MEN1 gene for mutations. In addition, exons 10 and 11 of the RET gene were sequenced. Results MEN1 mutations were found in 25 (22 per cent) of the 112 patients. Two patients had two simultaneous point-mutations. A total of 27 mutations were characterized, 24 of which have not been reported previously. There were seven nonsense mutations, ten frameshift mutations, two splice-site deletions, five missense mutations and three in-frame mutations. Nineteen mutations resulted in truncation of menin protein. Germline MEN1 mutations were found in three of 60 patients who had no family history of endocrine tumours associated with MEN1, and these patients were identified as MEN1 gene family probands. No somatic or germline RET exon 10 and 11 mutations were found in this series. Conclusion These findings suggest that MEN1 gene mutation may be associated not only with endocrine tumours of affected patients with MEN1 but also with sporadic parathyroid tumours. MEN1 gene analysis can distinguish inheritable from non-inheritable parathyroid tumours and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumours is necessary before parathyroid surgery.

Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations: analysis of 20 Japanese sporadic cases with MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is a familial tumour syndrome of endocrine tumours involving parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner with high penetrance. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned from chromosome 11q13. To characterize sporadic MEN1 patients, we analysed the MEN1 gene by direct sequencing of the entire open reading frame from 20 individuals. We identified heterozygous germline mutations of the MEN1 gene in 8 of 20 (40%) cases. Seven were novel MEN1 germline mutations. Three mutations were splicing abnormalities, and all were confirmed to be splicing defects by RT-PCR. The clinical significance of detecting germline MEN1 mutations, not only in familial MEN1 but also in sporadic MEN1, was confirmed by the finding of asymptomatic mutant carriers among family members of the sporadic MEN1 patients. Seven of 8 cases with MEN1 mutations had enteropancreatic lesions in contrast to 4 of 12 (P < 0.018) in those cases with no mutation. Ten of the 12 cases without MEN1 mutation were more than 50-year-old. Six of these 10 cases had the same clinical features; primary hyperparathyroidism and a GH-secreting pituitary tumour. It is likely that the six cases without mutations were MEN1 phenocopies due to (i) two kinds of tumours with high natural incidence in older subjects developed by chance (ii) another familial tumour syndrome with low penetrance, e. g. familial acromegaly with primary hyperparathyroidism by mutation of another gene, or (iii) somatic mutation during early embryonic stages.

Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1).

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome of endocrine tumors involving the parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned in 11q13. We aimed to assess the significance of MEN1 gene diagnostics in families with MEN1. Sixteen probands of familial MEN1 and their 40 family members were subjected to the study. Full-length sequencing of the open reading frame and exon-intron boundaries in the MEN1 gene was performed with probands of familial MEN1. Family members were examined for the identified mutation in the proband. We identified heterozygous germline mutations of the MEN1 gene in all of 16 Japanese MEN1 families examined, achieving the highest detectability of MEN1 mutations in familial MEN1 among studies that examined more than 10 families. Eleven kinds of the identified MEN1 germline mutations were novel. More than half were nonsense or frameshift mutations resulting in a premature stop codon (9/15; 60%), and no mutation hot spots or no apparent genotype-phenotype relationships were observed, in support of the results of other studies. We identified 40 mutant MEN1 gene carriers and 16 non-carriers in the course of the present study in those families. Analysis of the germline mutations in the MEN1 gene, providing significantly useful clinical information to probands and family members of MEN1, should be considered as a standard procedure and categorized as belonging to Group 1 cancer predisposition testing by the American Society of Clinical Oncology.

A novel splicing mutation (894-9 G→A) of the MEN1 gene responsible for multiple endocrine neoplasia type 1

Germline MEN1 gene mutations are responsible for multiple endocrine neoplasia type 1 (MEN1), a dominantly inherited cancer syndrome. We identified a MEN1 germline mutation 894-9 G→A in three MEN1 patients from two unrelated families. This mutation was not present in any of the 100 blood samples from normal volunteers. The wild type MEN1 sequence was lost in the patient's pancreatic tumor. Abnormal mRNA was identified in the tumor, which retained an intronic sequence indicating aberrant mRNA splicing at a newly created splicing acceptor site. These findings indicate that this nucleotide substitution is, though previously reported to be a polymorphism, a causative splicing mutation.

The gene for multiple endocrine neoplasia type 1: recent findings

Multiple endocrine neoplasia type 1 (MEN1) is a promising model to understand endocrine and other tumors. Its most common endocrine expressions are tumors of parathyroids, entero-pancreatic neuro-endocrine tissue, and anterior pituitary. Recently, collagenomas and multiple angiofibromas of the dermis also have been recognized as very common. MEN1 can be characterized from different perspectives: (a) as a hormone (parathyroid hormone, gastrin, prolactin, etc.) excess syndrome with excellent therapeutic options; (b) as a syndrome with sometimes lethal outcomes from malignancy of entero-pancreatic neuro-endocrine or foregut carcinoid tissues; or (c) as a disorder than can give insight about cell regulation in the endocrine, the dermal, and perhaps other tissue systems. The MEN1 gene was identified recently by positional cloning, a comprehensive strategy of narrowing the candidate interval and evaluating all or most genes in that interval. This discovery has opened new approaches to basic and clinical issues. Germline MEN1 mutations have been identified in most MEN1 families. Germline MEN1 mutations were generally not found in families with isolated hyperparathyroidism or with isolated pituitary tumor. Thus, studies with the MEN1 gene helped establish that mutation of other gene(s) is likely causative of these two MEN1 phenocopies. MEN1 proved to be the gene most frequent L4 mutated in common-variety, nonhereditary parathyroid tumor, gastrinoma, insulinoma, or bronchial carcinoid. For example, in common-variety parathyroid tumors, mutation of several other genes (such as cyclin D1 and P53) has been found, but much less frequently than MEN1 mutation. The majority of germline and somatic MEN1 mutations predicted truncation of the encoded protein (menin). Such inactivating mutations strongly supported prior predictions that MEN1 is a tumor suppressor gene insofar as stepwise mutational inactivation of both copies can release a cell from normal growth suppression. Menin is principally a nuclear protein; menin interacts with junD. Future studies, such as discovery of menin’s metabolic pathway, could lead to new opportunities in cell biology and in tumor therapy.

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.