Mutation Analysis of theMEN1Gene in Multiple Endocrine Neoplasia Type 1, Familial Acromegaly and Familial Isolated Hyperparathyroidism¹

Abstract

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia of the parathyroid glands, the endocrine pancreas, and the anterior pituitary gland. In addition, families with isolated endocrine neoplasia, notably familial isolated hyperparathyroidism (FIHP) and familial acromegaly, have also been reported. However, whether these families constitute MEN 1 variants or separate entities remains speculative as the genetic bases for these diseases are unclear. The gene for MEN 1 has recently been cloned and characterized. Using single strand conformation analysis (SSCA) and sequencing, we performed mutation analysis in: a) a total of 55 MEN 1 families from 7 countries, b) 13 isolated MEN 1 cases without family history of the disease, c) 8 acromegaly families, and d) 4 FIHP families. Mutations were identified in 27 MEN 1 families and 9 isolated cases. The 22 different mutations spread across most of the 9 translated exons and included frameshift (11), nonsense (6), splice (2), missense mutations (2), and in-frame deletions (1). Among the 19 Finnish MEN 1 probands, a 1466del12 mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was found in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common "warm" spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case one mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved and that additional such families need to be analyzed.

Molecular Genetics of Neuroendocrine Tumors

“…More than 300 different MEN1 germline mutations have now be identified in several independent national studies based on large series of MEN1 patients [22, 23, 24, 25, 26, 27]. Figure 1 shows the spectrum of most MEN1 mutations identified in France and recurrent mutations described by other groups.…”

“…Intronic and splice-junction mutations were reported in a few families and some of them were shown to alter RNA splicing with an abnormal exon skipping or intronic retention [28, 29]. Most mutations occurred once, while some of them were observed twice or more in apparently unrelated families [22, 23, 24, 25, 26, 27]. Haplotype analysis with 11q13 polymorphic markers demonstrated that most recurrent mutations were not related to a founder effect assessing the data from two independent linkage disequilibrium studies performed before the MEN1 gene was cloned [30].…”

Characterization of the mouse Men1 gene and its expression during development

“…The position of the epitope recognized by the antibody M1C2 is underlined. Below are indicated the position of constitutional (c) and somatic (s) missense mutations and single amino acid deletions detected in MEN 1 patients Agarwal et al, 1997;Bassett et al, 1998;Teh et al, 1998) and sporadic parathyroid Farnebo et al, 1998), pancreatic-duodenal (Toilat et al, 1997;Zhuang et al, 1997b) and pituitary tumours. For some amino acids more than one mutation was found, and the number is given in parenthesis (2 or 3) Uppercase and lowercase letters denote exonic and intronic sequences, respectively.…”

Stable overexpression of MEN1 suppresses tumorigenicity of RAS

“…The MEN1 gene was localized to 11q13 (Larsson et al, 1988) and later identi®ed by positional cloning . Mutation analysis of the MEN1 gene has so far revealed more than 200 MEN1 index cases with unique heterozygous germ-line mutations Bassett et al, 1998;Teh et al, 1998;Giraud et al, 1998;Poncin et al, 1999;Mutch et al, 1999). Analogous somatic mutations in the MEN1 gene are a major contributor to sporadic tumors: parathyroid adenomas, lung carcinoids, gastrinomas, insulinomas, and angio®bromas Debelenko et al, 1997;Zhuang et al, 1997;Boni et al, 1998).…”