A Large Germline Deletion of the MEN1 Gene in a Family with Multiple Endocrine Neoplasia Type 1

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome inherited as an autosomal dominant trait. Various heterozygous germline mutations of the responsible gene, MEN1, have been identified within its exons in many, but not all, affected individuals. We here demonstrate, by DNA polymorphism analysis and gene dosage analysis with polymerase chain reaction (PCR), a large heterozygous germline MEN1 deletion in a kindred with MEN1, in whom no mutation could be detected in the PCR-amplified exons. The deletion spanned an at least 7 kb region containing the entire MEN1 gene. These findings indicate that a large germline deletion of the MEN1 gene, which escapes detection in PCR-based sequence analysis, should be considered as a potential cause of MEN1.Key words: Multiple endocrine neoplasia type 1 -MEN1 -Tumor suppressor gene -Gene dosage -DNA testing Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid, enteropancreatic and pituitary tumors.1, 2) The responsible gene, MEN1, was recently identified on chromosome 11q13 by positional cloning. 3)A heterozygous MEN1 germline mutation underlies an inherited predisposition to the development of MEN1-related tumors. Although the molecular function of the encoded protein, menin, is unknown, 3) MEN1 is considered to be a tumor suppressor gene because loss of heterozygosity of the MEN1 locus frequently occurs in the MEN1-related tumors. 4)Previous studies have identified various MEN1 germline mutations within its exons in many affected individuals with MEN1.3, 5-8) Although several missense mutations and in-frame deletions have been identified, the detected germline mutations were mostly nonsense or frameshift mutations, which cause truncation of menin and, presumably, loss of function of the gene. These findings are consistent with a tumor suppressor function of this gene.The previous studies also revealed that some individuals affected with MEN1 had no detectable MEN1 germline mutation.3, 5-7) Because these studies analyzed only proteincoding exons that were amplified by polymerase chain reaction (PCR), a mutation in another region of the gene or a large heterozygous deletion could have been missed. Alternatively, some of these mutation-negative individuals could have had a distinct syndrome caused by some other gene(s) that meets the formal definition of MEN1 as suggested previously, 5) or could have had multiple independent tumors by chance in two or more MEN1-related endocrine tissues. Because identification of a MEN1 germline mutation enables presymptomatic recognition or early exclusion of this disease in individuals at risk, it is important to characterize MEN1 germline mutations which escape detection by PCRbased mutation screening.We encountered a case of familial MEN1 with three affected individuals, two of whom (Fig. 1, patients a and c) were previously analyzed and exhibited no detectable MEN1 germline mutation in the protein-coding exons. 7)We analyzed blood cell DNA of the third ...

A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

“…Microsatellite length polymorphism around the MEN1 locus was analyzed using polymorphic DNA markers on chromosome 11q13, PYGM and D11S4940, as described previously (19). PYGM and D11S4940 are located centromeric and telomeric, respectively, to the MEN1 gene.…”

Novel MEN1 gene mutations in familial multiple endocrine neoplasia type 1

“…However, it is to be noted that no mutations were found in some families with MEN 1 (Shimizu et al 1997;Bassett et al 1998). Some of these families may have a large deletion in the MEN1 gene (Kishi et al 1998), but a family with the clinical features of MEN 1 but not linked to Agarwal et al 1997;Shimizu et al 1997 d Bassett et al 1998 the MEN1 locus has also been reported (Stock et al 1997). Thus, absence of the MEN1 gene mutation, as determined by PCR and the following sequencing, cannot completely rule out the possibility that MEN 1 is present.…”

Novel germline mutations of the MEN1 gene in Japanese patients with multiple endocrine neoplasia type 1

“…This may stem from a mutation in the untranslated region, an intron or the promoter region of the gene, or a large germline deletion which resulted in amplification of only the normal copy of MEN1 by PCR. Indeed, a large germline deletion of the MEN1 gene is reported in a Japanese kindred (Kishi et al 1998). Our case 3 showed typical MEN1 phenotypes and the inheritance of the disease was verified at least in two generations (his brother and a nephew), although the heterogeneity of enteropancreatic tumors within the family exists (carcinoid tumor, gastrinoma, and insulinoma).…”