Germ-Line Mutation Analysis in Patients with Multiple Endocrine Neoplasia Type 1 and Related Disorders

• Published in: American journal of human genetics Vol. 63; no. 2; pp. 455 - 467
• Main Authors: Giraud, Sophie, Zhang, Chang X., Serova-Sinilnikova, Olga, Wautot, Virginie, Salandre, Janine, Buisson, Nathalie, Waterlot, Christine, Bauters, Catherine, Porchet, Nicole, Aubert, Jean-Pierre, Emy, Philippe, Cadiot, Guillaume, Delemer, Brigitte, Chabre, Olivier, Niccoli, Patricia, Leprat, Frédéric, Duron, Francoise, Emperauger, Brigitte, Cougard, Patrick, Goudet, Pierre, Sarfati, Emile, Riou, Jean-Paul, Guichard, Sylvie, Rodier, Michel, Meyrier, Alain, Caron, Philippe, Vantyghem, Marie-Christine, Assayag, Michel, Peix, Jean-Louis, Pugeat, Michel, Rohmer, Vincent, Vallotton, Michel, Lenoir, Gilbert, Gaudray, Patrick, Proye, Charles, Conte-Devolx, Bernard, Chanson, Philippe, Shugart, Yin Y., Goldgar, David, Murat, Arnaud, Calender, Alain
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-08-1998; University of Chicago Press
• Subjects: Amino Acid Substitution; Biological and medical sciences; Endocrine pancreas. Apud cells (diseases); Endocrine tumors; Endocrinopathies; Exons; Female; Genetic Carrier Screening; Germ-Line Mutation; Humans; Introns; Male; Medical sciences; MEN1; Menin; Multiple Endocrine Neoplasia - classification; Multiple Endocrine Neoplasia - genetics; Multiple Endocrine Neoplasia Type 1 - classification; Multiple Endocrine Neoplasia Type 1 - genetics; Mutation; Mutation(s); Mutation, Missense; Neoplasia; Neoplasm Proteins - genetics; Pedigree; Point Mutation; Predisposition; Proto-Oncogene Proteins; Sequence Deletion; Tumors. Hypoglycemia; Mutation(s); Neoplasia; Endocrine tumors; Predisposition; Menin; MEN1; Endocrinopathy; Human; Family study; Exploration; Genotype; Genetic determinism; Genetic disease; Multiple endocrine neoplasia type I; Phenotype; Gene; Germ line; Genetics; Benign neoplasm; Mutation; Molecular biology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/301953

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.