This Article Full Text Full Text (PDF) Supplemental Data A correction has been published Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Agarwal, S. K. Articles by Marx, S. J. Search for Related Content PubMed PubMed Citation Articles by Agarwal, S. K. Articles by Marx, S. J. Related Collections Neuroendocrinology and Pituitary Cardiovascular Endocrinology Endocrine Oncology

Rare Germline Mutations in Cyclin-Dependent Kinase Inhibitor Genes in Multiple Endocrine Neoplasia Type 1 and Related States

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Sunita K. Agarwal, Ph.D., Building 10, Room 9C-103, National Institutes of Health, Bethesda, Maryland 20892-1802. E-mail: SunitaA{at}mail.nih.gov.

Context: Germline mutation in the MEN1 gene is the usual cause of multiple endocrine neoplasia type 1 (MEN1). However, the prevalence of identifiable germline MEN1 mutations in familial MEN1 cases is only 70%. Some cases may have a germline mutation in another gene such as the p27 cyclin-dependent kinase inhibitor (CDKI).

Objective: The aim of the study was to investigate cases of MEN1 or related states for germline mutations in all CDKI genes.

Methods: A total of 196 consecutive index cases were selected with clear or suspected MEN1 and no identifiable germline MEN1 mutation. Every case was analyzed for germline mutation in each of the seven CDKI genes.

Results: We identified benign polymorphisms of the CDKI genes and also 15 other initially unclassified sequence variants. After detailed gene/protein analysis, seven of these 15 variants were classified as probably pathological mutations. Three of these seven were probable mutations of p27. The remaining four were probable pathological mutations in three of the other CDKI genes, thereby implicating these three genes in the germline of human tumors. The identification rates for probably pathological mutations among the 196 index cases were similarly low for each of four CDKI genes: p15 (1%), p18 (0.5%), p21 (0.5%), and p27 (1.5%). No characteristic clinical subtype related to MEN1 was identified among the seven index cases and their families.

Conclusion: Rare germline mutation in any among four (p15, p18, p21, and p27) of the seven CDKIs is a probable cause of MEN1 or of some related states.

This article has been cited by other articles:

				A. Falchetti and M. L. Brandi Multiple Endocrine Neoplasia Type I Variants and Phenocopies: More than a Nosological Issue? J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1518 - 1520. [Full Text] [PDF]