Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders

Sophie Giraud, Chang X. Zhang, Olga Serova-Sinilnikova, Virginie Wautot, Janine Salandre, Nathalie Buisson, Christine Waterlot, Catherine Bauters, Nicole Porchet, Jean Pierre Aubert, Philippe Emy, Guillaume Cadiot, Brigitte Delemer, Olivier Chabre, Patricia Niccoli, Frédéric Leprat, Francoise Duron, Brigitte Emperauger, Patrick Cougard, Pierre GoudetEmile Sarfati, Jean Paul Riou, Sylvie Guichard, Michel Rodier, Alain Meyrier, Philippe Caron, Marie Christine Vantyghem, Michel Assayag, Jean Louis Peix, Michel Pugeat, Vincent Rohmer, Michel Vallotton, Gilbert Lenoir, Patrick Gaudray, Charles Proye, Bernard Conte-Devolx, Philippe Chanson, Yin Y. Shugart, David Goldgar, Arnaud Murat, Alain Calender

Research output: Contribution to journalArticlepeer-review

180 Scopus citations


Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ- line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68.5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.

Original languageEnglish (US)
Pages (from-to)455-467
Number of pages13
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 1998
Externally publishedYes

ASJC Scopus subject areas

  • Genetics


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