A Novel Isogenic Human Cell-Based System for MEN1 Syndrome Generated by CRISPR/Cas9 Genome Editing

Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome that manifests differently among various patients. Despite the mutations in the MEN1 gene that commonly predispose tumor development, there are no obvious phenotype–genotype correlations. The existing animal and in vitro models do not allow for studies of the molecular genetics of the disease in a human-specific context. We aimed to create a new human cell-based model, which would consider the variability in genetic or environmental factors that cause the complexity of MEN1 syndrome. Here, we generated patient-specific induced pluripotent stem cell lines carrying the mutation c.1252G>T, D418Y in the MEN1 gene. To reduce the genetically determined variability of the existing cellular models, we created an isogenic cell system by modifying the target allele through CRISPR/Cas9 editing with great specificity and efficiency. The high potential of these cell lines to differentiate into the endodermal lineage in defined conditions ensures the next steps in the development of more specialized cells that are commonly affected in MEN1 patients, such as parathyroid or pancreatic islet cells. We anticipate that this isogenic system will be broadly useful to comprehensively study MEN1 gene function across different contexts, including in vitro modeling of MEN1 syndrome.

IS THAT THE R171Q AMINO ACID VARIANT IN EXON 3 OF THE MEN1 GENE IS RELATED TO AGE, TO PLAY A MUTATING ROLE?

Background/aim: Several studies demonstrated that the R171Q amino acid variant in exon 3 of MEN1 gene is a polymorphism, and in some new studies it is probably a mutation. We found in our study of twelve cases, two young cases have this variant and developed multiple endocrine neoplasia type1. Materials and methods: twelve MEN1 young patients (7 female, 5 male) aged between 20 and 40 years old, were included in our study. After investigating each patient, biochemical and molecular researches is done. We sequenced exon 3 of the MEN1 gene of patients and some members of their families. Results: Ten patients have MEN1 syndrome and they have no mutation in MEN1 gene. Two patients from separated families have a c.512G>A heterozygote variant. Phenotypically the two cases have hyperparathyroidism in young age. One of them developed others tumors later. Conclusion: The R171Q variant is a mutation in some cases; causes hyperparathyroidism and will develop further MEN1 lesions later, and it is just a polymorphism in other cases. We believe that when this polymorphism combines with young age in severe depression, it will lead to MEN1 syndrome, which will make this polymorphism considered a genetic mutation

A novel mutation of the MEN1 gene in a patient with multiple endocrine neoplasia type 1 and recurrent fibromyxoid sarcoma – a case report

Background Multiple endocrine neoplasia type 1 (MEN1) syndrome is usually accompanied by endocrine tumors, but non-endocrine tumors can occur as well. However, the coexistence of MEN1 syndrome and malignant tumor such as low-grade fibromyxoid sarcoma has not been described in the literature. Moreover, the MEN1 gene mutations have not been identified in patients with fibromyxoid sarcoma, so far. Case presentation We present a patient with a long-year endocrine follow-up due to multiple endocrine tumors. During his lifespan, he has been surgically treated for pancreatic gastrinoma, parathyroid hyperplasia, atypical pulmonary carcinoid, various benign mesenchymal, and several skin tumors (basocellular tumor, lipomas, and fibromas) which raised a high clinical suspicion of MEN1 syndrome but the patient refused genetic testing. Recently, he developed a novel malignant tumor – recurrent low-grade fibromyxoid sarcoma of the trunk and extremities with multiple subsequent operations. The patient eventually accepted the genetic testing which proved him to be a carrier of a novel mutation in the MEN1 gene. Conclusions Unlike some other syndromes where a genetic mutation can predict clinical course, there is no genotype-phenotype correlation in MEN1 syndrome. Therefore, these patients require lifelong and multidisciplinary surveillance, not only for typical endocrine and benign non-endocrine tumors but also for diverse and even more malignant forms. The atypical clinical presentation should pose suspicion about new gene mutation and serve as a warning in the further follow-up.

The Genetic Multiplicity- Multiple Endocrine Neoplasia type I

Multiple endocrine neoplasia type 1 (MEN1) is a syndrome emerging from characteristic mutations of MEN1 gene with concurrently enunciated multiple endocrine and tumours and associated non-endocrine neoplasm. Previously designated as Werner’s syndrome, MEN1 syndrome denominates genomic mutation within chromosome 11q13 or a tumour suppressor gene with a distinctive protein product nomenclated as “menin”. MEN1 syndrome demonstrates an autosomal dominant pattern of disease inheritance where genomic mutations delineate a comprehensive (100%) disease penetrance. MEN1 gene was initially identified in 1997 upon chromosome 11q13. Although twelve genetic mutations were primarily identified, currently beyond eighteen hundred genomic mutations are scripted1, 2. MEN1 syndrome is comprised of diverse combination of twenty or more endocrine and non-endocrine tumours exemplifying a classic triad of pituitary, parathyroid and pancreatic neoplasm. Diverse non endocrine tumours enunciated with MEN1 syndrome are denominated with meningioma, ependymoma or angiofibroma1, 2. Endocrine tumours are discerned on account of excessive hormonal secretion engendered from various neoplasm or on account of neoplastic evolution. Approximately 10% instances can occur due to a de-novo genomic variant. Offspring of an individual with MEN1 syndrome quantifies a 50% possibility of inheriting the genomic variant. Cogent prenatal diagnosis can be determined in instances where specific genomic variant of a particular family is known. Physical, psychological and social restrictions are prevalent with MEN1 syndrome. Heterozygotes with MEN1 genetic variant are denominated as carriers and manifest a two- fold possible mortality1, 2.