Characterization of Mutations in Patients with Multiple Endocrine Neoplasia Type 1

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified. We have characterized such MEN1 mutations, assessed the reliability of SSCP analysis for the detection of these mutations, and estimated the age-related penetrance for MEN1. Sixty-three unrelated MEN1 kindreds (195 affected and 396 unaffected members) were investigated for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. We identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice-site mutation, and 6 missense mutations), that were scattered throughout the coding region, together with six polymorphisms that had heterozygosity frequencies of 2%-44%. More than 10% of the mutations arose de novo, and four mutation hot spots accounted for >25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected >85% of the mutations. Two hundred and one MEN1 mutant-gene carriers (155 affected and 46 unaffected) were identified, and these helped to define the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. These results provide the basis for a molecular-genetic screening approach that will supplement the clinical evaluation and genetic counseling of members of MEN1 families.

A MEN1 syndrome with a paraganglioma

“…Indeed, the penetrance of MEN1 for 20-and 25-year-old mutation carriers is estimated around 52% and 78%, respectively. 12 Genetic testing permitted to enable a strict follow-up for these two patients and to avoid periodic screening of non-carriers.…”

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.…”

Multiple endocrine neoplasia phenocopy revealed as a co‐occurring neuroendocrine tumor and familial hypocalciuric hypercalcemia type 3

“…In addition, the patient was negative for all mutations known to cause MEN1, although about 5–15% of considered MEN1 cases are genetically unverified 17, 23, 24. Furthermore, only the index patient had affection of more than one organ, and as the penetrance of MEN1 is close to 100% in patients older than 50 years, it is unlikely that the 71‐year‐old father should be unaffected 20, 25. The low CCCR is also not typical for PHPT, but can occur due to low vitamin D. According to Thakker et al, MEN1 phenocopies are seen in up to 10% of cases with the causative mutations found in other genes including CDC73 and CASR .…”