Genetic background influences embryonic lethality and the occurrence of neural tube defects in Men1 null mice: relevance to genetic modifiers

Lemos, Manuel C.; Harding, Brian; Reed, Anita; Jeyabalan, Jeshmi; Walls, Gerard; Bowl, Michael R.; Sharpe, James; Wedden, Sarah; Moss, Julie; Ross, Allyson; Davidson, Duncan; Thakker, Rajesh V.

doi:10.1677/joe-09-0124

Cited by 38 publications

(34 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly and consistent with the data from humans presented herein, the effects of genetic background and modifiers on the phenotype of embryonic lethality in Men1-knockout mouse models have been demonstrated previously. By backcrossing Men1 C/K mice, the authors generated the C57BL/6 and 129S6/SuEv strains; a significant early lethality in the 129S6/SuEv strain was found after analyzing a large number of embryos (32). These data underline the importance of the genetic background in influencing the MEN1 phenotype and implicate a role for genetic modifiers in this syndrome in mice, in a finding parallel to the data presented herein for humans.…”

Section: Discussionsupporting

confidence: 64%

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Longuini

Lourenço

Sekiya

et al. 2014

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. Design: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Methods: Genotyping of the coding p27 c.326TOG (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. Results: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (ORZ2.55, PZ0.019, CIZ1.013-5.76). Among patients who are R30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; ORZ18.33; PZ0.002, CIZ2. 88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. European Journal of EndocrinologyClinical Study V C Longuini and others p27 rs2066827, an MEN1 syndrome modifier

show abstract

Section: Discussionsupporting

confidence: 64%

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Longuini

Lourenço

Sekiya

et al. 2014

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Mice having tissue-specific knock-out of the Men1 gene in parathyroid, pituitary, or pancreatic ␤-cells develop normally, suggesting that menin does not influence development of these tissues (13)(14)(15)(16). However, constitutively null Men1 Ϫ/Ϫ mice die in utero at midgestation of multiple defects in developing organs, suggesting that menin is critical for normal development (10,17,18). The fetuses are small and have craniofacial defects suggesting that menin might play a role in both endochondral and intramembranous bone formation (10,17).…”

Section: Discussionmentioning

confidence: 99%

“…Mice that are constitutively homozygous null for the Men1 gene die in utero at mid-gestation of multiple defects in developing organs, suggesting that menin does play critical essential roles in tissues additional to those affected in the MEN1 syndrome (10,17,18). The fetuses are small and exhibit craniofacial defects, suggesting that menin might play a role in both endochondral and intramembranous bone formation (10,17).…”

mentioning

confidence: 99%

Osteoblast Menin Regulates Bone Mass in Vivo

Kanazawa¹,

Canaff²,

Abi‐Rafeh³

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Moreover, it is hypothetically possible that yet-to-be-identified modifier genes might attenuate clinical expression even in families with unstable mutant menin. (34) Nevertheless, patients having unstable missense or indel menin mutations as well as those having truncated mutations should be strictly treated as a mutation carrier of typical MEN1. (35) Because previous studies failed to relate specific MEN1 mutations to a particular clinical phenotype, all mutation carriers have been considered to require full screening of MEN1-related tumors and lifelong follow up.…”

Section: Discussionmentioning

confidence: 99%

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Shimazu¹,

Nagamura²,

Yaguchi

et al. 2011

Cancer Science

View full text Add to dashboard Cite

Germline mutations of the tumor suppressor gene MEN1 are found not only in typical multiple endocrine neoplasia type 1 (MEN1) but also in its incomplete forms such as familial isolated hyperparathyroidism (FIHP) and apparently sporadic parathyroid tumor (ASPT). No definitive genotype-phenotype correlation has been established between these clinical forms and MEN1 gene mutations. We previously demonstrated that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. To examine whether the intracellular stability of mutant menin is correlated with clinical phenotypes, we developed a method of evaluating menin stability and examined 20 mutants associated with typical MEN1 (17 missense, two in-frame deletion, one nonsense) and 21 mutants associated with FIHP or ASPT (19 missense, two in-frame deletion). All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1. Some stable mutants exhibited substantial biological activities when tested by JunD-dependent transactivation assay. These findings suggest that certain missense and in-frame mutations are fairly stable and retain intrinsic biological activity, and might be specifically associated with incomplete clinical phenotypes. The menin stability test will provide useful information for the management of patients carrying germline MEN1 mutations especially when they have missense or in-frame variants of ambiguous clinical significance. (Cancer Sci 2011; 102: 2097-2102 M enin is a tumor suppressor protein encoded by MEN1, a gene responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome typically characterized by the development of multiple tumors in the pituitary, parathyroid and enteropancreatic endocrine tissues.(1,2) Menin is a nuclear protein having C-terminal nuclear localizing signal sequences, (3) and exhibits modulatory activity on gene expression such as repression of JunD-dependent transcription. (4) Diverse roles have been implicated for menin, including cell cycle control, cell differentiation and DNA repair, which are likely to be conferred by interaction with various menin-binding proteins.(2) Menin is considered to be a scaffold protein tethering such proteins to specific gene loci.(5) Although the mechanism of how menin is involved in gene regulation has been elucidated to some extent, the basis for tissue-specific tumorigenesis in MEN1 remains unknown.Heterozygous germline mutations of the MEN1 gene are found in 70-90% of patients clinically diagnosed as MEN1. (6) More than 500 different loss-of-function mutations have been identified, which are distributed throughout the gene with no apparent hot spot.(2,6,7) Germline MEN1 mutations have also been found in a subset of familial isolated hyperparathy...

show abstract

Genetic background influences embryonic lethality and the occurrence of neural tube defects in Men1 null mice: relevance to genetic modifiers

Cited by 38 publications

References 56 publications

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations

Osteoblast Menin Regulates Bone Mass in Vivo

Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms

Contact Info

Product

Resources

About