Deletion of exons 1–3 of the MEN1 gene in a large Italian family causes the loss of menin expression

Zatelli, Maria Chiara; Tagliati, Federico; Ruvo, Mauro Di; Castermans, Emilie; Cavazzini, Luigi; Daly, Adrian; Ambrosio, Maria Rosaria; Beckers, Albert; Uberti, Ettore C. degli

doi:10.1007/s10689-014-9702-y

Cited by 7 publications

(10 citation statements)

References 27 publications

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“…In particular, a novel gross deletion (exon 5, 6) of MEN1 gene was detected by MLPA in one of the families. Till now, 14 MEN1 gross deletions have been reported, including 5 partial gene deletions and 9 whole gene deletions [6, 30–33]. Our result reinforces the current recommendation for screening exonic deletions using MLPA in patients, who match the clinical manifestation of MEN1 but with no mutations detected by direct DNA sequencing [2].…”

Section: Discussionsupporting

confidence: 84%

Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese

Kong¹,

Wang²,

Nie³

et al. 2016

PLoS ONE

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ObjectiveMultiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) differs in many aspects from sporadic PHPT (SHPT). The aims of this study were to summarize the clinical features and genetic background of Chinese MHPT patients and compare the severity of the disease with those of SHPT.Design and MethodsA total of 40 MHPT (27 sporadic, 7 families) and 169 SHPT cases of Chinese descent were retrospectively analyzed. X-rays and ultrasound were used to assess the bone and urinary system. Dual energy x-ray absorptiometry (DXA) were performed to measure bone mineral density (BMD). Besides direct sequencing of the MEN1 and CDKN1B genes, multiplex ligation-dependent probe amplification (MLPA) was used to screen gross deletion for the MEN1 gene.ResultsCompared with SHPT patients, MHPT patients showed lower prevalence of typical X-ray changes related to PHPT (26.3% vs. 55.7%, P = 0.001) but higher prevalence of urolithiasis/renal calcification (40.2% vs. 60.0%, P = 0.024). MHPT patients showed higher phosphate level (0.84 vs. 0.73mmol/L, P<0.05) but lower ALP (103.0 vs. 174.0U/L, P<0.001) and PTH (4.0 vs. 9.8×upper limit, P<0.001) levels than SHPT patients. There were no significant differences in BMD Z-scores at the lumbar spine and femoral neck between the two groups. Mutations in the MEN1 gene were detected in 27 MHPT cases. Among the nine novel mutations were novel, one of them involved the deletion of exon 5 and 6.ConclusionsMHPT patients experienced more common kidney complications but less skeletal issues, and a milder biochemical manifestation compared with SHPT patients. MEN1 mutation detection rate was 79.4% and 9 of the identified mutations were novel.

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Section: Discussionsupporting

confidence: 84%

Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese

Kong¹,

Wang²,

Nie³

et al. 2016

PLoS ONE

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“…This patient was also characterized by the development of aggressive pNENs and a malignant jejunal NET, both, with metastases that developed during short term follow-up of 2–5 years. Based on this very limited data one could hypothesize that MEN1 patients with large gene deletion might develop a more aggressive form of disease, which was also reported by other authors (24) (25) (26) . On the other hand, there are also some studies revealing no special correlation between aggressive disease and mutation type (4) (19) .…”

Section: Discussionsupporting

confidence: 78%

An unusual phenotype of MEN1 syndrome with a SI-NEN associated with a deletion of the MEN1 gene

Manoharan

Lopez

Hackmann

et al. 2016

Endocrinology, Diabetes &Amp; Metabolism Case Reports

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SummaryWe report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation.Learning points Our patient presents an extraordinary course of disease.Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

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“…Gross deletions, usually detected by the MLPA technique (20)(21)(22)(23), are the rarest kind of MEN1 mutation. The complete MEN1 gene deletion has been considered by different authors (20,24,25).…”

Section: Discussionmentioning

confidence: 99%

“…The complete MEN1 gene deletion has been considered by different authors (20,24,25). The rst (exons 1-3) (22,23), central (exons 5-6) (21), and nal (exons 8-10) regions of the gene (26) have been described by other gross deletions. Beijers et al (12) were the rst to report on a family with combined germline and somatic mosaicism for MEN1.…”

Section: Discussionmentioning

confidence: 99%

Multiple Endocrine Neoplasia Type 1: A Chinese Family with a new germline mutation(c.201delC) and A Detection Errors due to Intron Mutation

Zhang

Lin

Wang

et al. 2020

Preprint

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Background: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline mutations in the MEN1 gene located on chromosome 11q13. The three main endocrine tissues affected most frequently by tumors in MEN1 are the parathyroid (95%), enteropancreatic neuroendocrine tissues (50%), and anterior pituitary (40%). The purpose of this study was to report on a Chinese family with a new heterozygous MEN1 mutation in exon 2 [NM_130802: c.201delC (p.Ala68Profs*51) with localization to Chr11:64577381 on assembly GRCh37].Methods: A 49-year-old female patient (proband) was admitted to the hospital due to intermittent recurrent hypoglycemia symptoms. After a series of examinations, we found that she had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicious gastrinoma. Due to the proband’s suspicious clinical manifestations of MEN1, we performed genetic detection for the proband and her immediate family members. To rule out homozygous mutations caused by deletion of gene fragments, the proband and her immediate family members were detected the MLPA (Multiplex ligation-dependent probe amplification).Results: A new MEN1 germline mutation [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found by the genetic test. Two of the proband’s six relatives were found by the genetic test to have the same mutations as the proband, and the proband’s sister has the typical symptoms of MEN1 as well. However, the first time and second time genetic detection results showed that they were homozygous mutation, it didn’t conform to Mendelian inheritance laws. The MLPA results showed that the gene deletion was absent in the MEN1. The third time genetic detection (redesigned the prime) showed that they were heterozygous mutation. This detection errors due to intron mutation.Conclusions: A new germline mutation that induced MEN1, which can improve the identification of clinical phenotypes of MEN1 and the early diagnosis of the disease, was identified. Intron mutation may lead to wrong results of homozygous, which incompatible with Mendelian genetic law. Redesign the primer for gene detection could avoid this situation.

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Deletion of exons 1–3 of the MEN1 gene in a large Italian family causes the loss of menin expression

Cited by 7 publications

References 27 publications

Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese

Clinical and Genetic Analysis of Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism in Chinese

An unusual phenotype of MEN1 syndrome with a SI-NEN associated with a deletion of the MEN1 gene

Multiple Endocrine Neoplasia Type 1: A Chinese Family with a new germline mutation(c.201delC) and A Detection Errors due to Intron Mutation

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