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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 8 2621-2626
Copyright © 1998 by The Endocrine Society

Original Studies

Mutation Analysis of the MEN1 Gene in Multiple Endocrine Neoplasia Type 1, Familial Acromegaly and Familial Isolated Hyperparathyroidism1

Mutation analysis group: B. T. Teh, S. Kytölä, F. Farnebo, L. Bergman, F. K. Wong, G. Weber, N. Hayward and C. Larsson

Clinical diagnosis group: B. Skogseid, A. Beckers, C. Phelan, M. Edwards, M. Epstein, F. Alford, D. Hurley, S. Grimmond, G. Silins, M. Walters, C. Stewart, J. Cardinal, S. Khodaei, F. Parente, L. Tranebjærg, R. Jorde, J. Menon, A. Khir, T. T. Tan, S. P. Chan, A. Zaini, B. A. K. Khalid, K. Sandelin, N. Thompson, M.-L. Brandi, M. Warth, J. Stock, J. Leisti, D. Cameron, J. J. Shepherd, K. Öberg, M. Nordenskjöld and P. Salmela

Endocrine Tumor (B.T.T., S.Ky., F.F., F.K.W., C.L., C.P.) and Clinical Genetics Units (G.W., S.Kh., P.F., and M.N.), Department of Molecular Medicine, Karolinska Hospital, Sweden; Departments of Clinical Genetics (S.Ky., J.L.) and Internal Medicine (P.S.), Oulu University Hospital, Finland; Queensland Institute of Medical Research (L.B., N.H., G.S., M.W., C.S.), Princess Alexandra Hospital (J.C., D.C.), Hunter Area Health Service (M.Ed.); Princeton Medical Centre Hamilton (M.Ep.); Royal Perth Hospital (D.H.); St. Vincents Hospital (F.A.); Royal Hobart Hospital (J.J.S.), Australia; Department of Internal Medicine, Uppsala University Hospital, Sweden (B.S., K.Ö.); Department of Endocrinology, Sart Tilman University Hopital, Liège, Belgium (A.B.); Departments of Medical Genetics (L.T.) and Internal Medicine (R.J.), University Hospital of Tromsø, Norway; Department of Medicine (J.M.), Queen Elisabeth Hospital, Kuta Kinabalu, Sabah, Malaysia; Faculty of Medicine, University of Malaya (A.K., S.P.C., A.Z.), University Kebangsaan Malaysia (T.T.T., B.A.K.K) Kuala Lumpur, Malaysia; University of Michigan Hospital (N.T.), Ann Arbor, Michigan; Department of Clinical Physiopathology (M.-L.B.), University of Florence, Italy; Endocrinology, Memorial Hospital (M.W., J.S.), Worcester, Massachussets

Address all correspondence and requests for reprints to: Catharina Larsson, M.D., Ph.D., Endocrine Tumor Unit, Department of Molecular Medicine, Karolinska Hospital CMM L8:01, S-171 76 Stockholm, Sweden. E-mail: Catharina.Larsson{at}cmm.ki.se

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.




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