Analysis of recurrent germline mutations in theMEN1 gene encountered in apparently unrelated families

Agarwal, Sunita; Debelenko, Larisa V.; Kester, Mary Beth; Guru, Siradanahalli C.; Manickam, Pachiappan; Olufemi, Shodimu-Emmanuel; Skarulis, Monica C.; Heppner, Christina; Crabtree, Judy S.; Lubensky, Irina A.; Zhuang, Zhengping; Kim, Young S.; Chandrasekharappa, Settara C.; Collins, Francis S.; Liotta, Lance A.; Spiegel, Allen M.; Burns, A. Lee; Emmert‐Buck, Michael R.; Marx, Stephen J.

doi:10.1002/(sici)1098-1004(1998)12:2<75::aid-humu1>3.0.co;2-t

Cited by 36 publications

(16 citation statements)

References 23 publications

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“…In this sense, several mutations occur in regions of DNA that could be prone to DNA polymerase slippage during DNA replication due to short DNA sequence repeat motifs. 14 The existence of CT and CA dinucleotide repeats has been observed flanking the 4 bp deletions in the vicinity of the codons 83/84 in exon 2, and codons 210/211 in exon 3 respectively, consistent with a replication slippage model. A similar (Figure 1), located in exon 4, could be explained by the formation of a hairpin loop structure (Figure 2) as has been already described in other diseases.…”

Section: Discussionmentioning

confidence: 60%

“…This model could demonstrate that the dinucleotide repeats surrounding some of the insertions or deletions found in the MEN 1 gene are involved in the appearance of these mutational events, as has been suggested by other authors. 8,14 In family 2 only the proband showed clinical symptoms of MEN 1 and carried a mutation in exon 2. By means of sequencing and haplotype analysis we could not confirm with 100% reliability that this was a de novo mutation, because the proband and his healthy brother had different paternal chromosomes.…”

Section: Discussionmentioning

confidence: 99%

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Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1

et al. 1999

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Multiple endocrine neoplasia type 1 (MEN 1) is characterised by the combination of tumours of the parathyroid, endocrine pancreas and anterior pituitary glands. In 1988 the MEN 1 gene was mapped to chromosome 11q13 and it was cloned in 1997. This gene contains 10 exons and extends across 9 Kb of genomic DNA; it encodes for a product of 610 amino acid named menin whose function is unknown. We have studied 10 unrelated MEN 1 kindreds by a complete sequencing analysis of the entire gene; mutations were identified in nine of them: five deletions, one insertion, two nonsense mutation and a complex alteration consisting of a deletion and an insertion that can be explained by a hairpin loop model. Two of the mutations have been previously described; the other seven were novel, and they were scattered throughout the coding sequence of the gene. As in previous series, no correlation was found between phenotype and genotype.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1

et al. 1999

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“…However, the authors only sequenced the exons 2±10 of the MEN1 gene if LOH on 11q13 was detected. LOH analysis was performed using three microsatellite markers at chromosome 11q13 (PYGM, INT-2 and D11S906) spanning a relatively large area of at least 1.2 Mb (22). Therefore, this study could have missed tumours with somatic MEN1 gene mutations and very small allelic deletions on 11q13 not detected with the above mentioned technique.…”

Section: Discussionmentioning

confidence: 99%

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism

Miedlich¹,

Krohn²,

Lamesch³

et al. 2000

European Journal of Endocrinology

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Objectives: Investigation of small numbers of parathyroid tumours by X-chromosome inactivation analysis suggests that the majority of them are monoclonal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identi®ed in 12±17% of solitary parathyroid tumours in patients with sporadic primary hyperparathyroidism, and they may be the precipitating genetic defect leading to monoclonal cell proliferation in these tumours. Design: To determine the prevalence of MEN1 gene mutations in monoclonal parathyroid neoplasias we investigated 33 parathyroid tumours of patients with primary hyperparathyroidism for clonality and mutations in the MEN1 gene. Methods: X-chromosome inactivation analysis was used to assess the clonal status of the tumours, direct sequencing of the complete coding region was applied to identify mutations in the MEN1 gene. Results: Twenty-eight female patients (26 patients with solitary adenoma, 2 patients with hyperplasia) were informative for the polymorphism of the androgen receptor on the X-chromosome and could be tested for inactivation pattern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Somatic mutations in the MEN1 gene were identi®ed in nine cases. Six of them were found in the relatively large second exon of the MEN1 gene (A49D, 193del36, 402delC, 482del22, 547delT, W126X). One was found in exon 5 (904del9), one in exon 7 (Y327X) and one in exon 9 (R415X). Of the monoclonal tumours, 5 out of 19 (26%) harboured a somatic MEN1 gene mutation. Conclusions: In summary, 73% of the solitary parathyroid adenomas were monoclonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has been identifed. However, for 74% of monoclonal tumours of the parathyroids the underlying genetic defects are still not known.

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“…Only 13 founder effects have been reported so far in this disease (Supplemental Table 4, which can be viewed online at http://www.eje-online.org/supplemental/; 14, 28-30, 49-51). The description of the full MEN1 phenotype was available in six of these cases, coinciding with the very large families analyzed here (Table 4) (14,(28)(29)(30). The founder effect documented in the present MEN1 family is the first reported in Latin America.…”

Section: Founding Mutationmentioning

confidence: 93%

“…Notably, all five previously reported very large MEN1 genealogies were associated with founder chromosomes (12,13,25,26). Founder effects were documented in these five very large families by combining genetic studies (same germline MEN1 mutation and common haplotype) and clinical investigations with genealogical data associated with a common geographic origin (12)(13)(14)(25)(26)(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 93%

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

Lourenço¹,

Toledo²,

Mackowiak³

et al. 2008

European Journal of Endocrinology

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Objective: Only few large families with multiple endocrine neoplasia type 1 (MEN1) have been documented. Here, we aimed to investigate the clinical features of a seven-generation Brazilian pedigree, which included 715 at-risk family members. Design: Genealogical and geographic analysis was used to identify the MEN1 pedigree. Clinical and genetic approach was applied to characterize the phenotypic and genotypic features of the family members. Results: Our genetic data indicated that a founding mutation in the MEN1 gene has occurred in this extended Brazilian family. Fifty family members were diagnosed with MEN1. Very high frequencies of functioning and non-functioning MEN1-related tumors were documented and the prevalence of prolactinoma (29.6%) was similar to that previously described in prolactinoma-variant Burin (32%). In addition, bone mineral density analysis revealed severe osteoporosis (T, K2.87G0.32) of compact bone (distal radius) in hyperparathyroidism (HPT)/MEN1 patients, while marked bone mineral loss in the lumbar spine (T, K1.95G0.39), with most cancellous bone, and femoral neck (mixed composition; T, K1.48G0.27) were also present. Conclusions: In this study, we described clinically and genetically the fifth largest MEN1 family in the literature. Our data confirm previous findings suggesting that prevalence of MEN1-related tumors in large families may differ from reports combining cumulative data of small families. Furthermore, we were able to evaluate the bone status in HPT/MEN1 cases, a subject that has been incompletely approached in the literature. We discussed the bone loss pattern found in our MEN1 patients comparing with that of patients with sporadic primary HPT.European Journal of Endocrinology 159 259-274

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Analysis of recurrent germline mutations in theMEN1 gene encountered in apparently unrelated families

Cited by 36 publications

References 23 publications

Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1

Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism

Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile

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