Horm Metab Res 2009; 41(8): 630-634
DOI: 10.1055/s-0029-1216358
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

An Intronic Mutation is Associated with Prolactinoma in a Young Boy, Decreased Penetrance in his Large Family, and Variable Effects on MEN1 mRNA and Protein

L. Drori-Herishanu 1 , A. Horvath 1 , M. Nesterova 1 , Y. Patronas 1 , M. Lodish 1 , 2 , E. Bimpaki 1 , N. Patronas 3 , S. Agarwal 4 , R. Salvatori 5 , M. Martari 1 , V. Mericq 6 , C. A. Stratakis 1 , 2
  • 1Section of Endocrinology and Genetics, Program on Developmental Endocrinology Genetics (PDEGEN), NIH, Bethesda, Maryland, USA
  • 2Pediatric Endocrinology Inter-Institute Training Program (PEITP), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), NIH, Bethesda, Maryland, USA
  • 3Department of Diagnostic Radiology, National Institutes of Health (NIH) Clinical Center, NIH, Bethesda, Maryland, USA
  • 4Metabolic Diseases Branch, National Institute on Diabetes AND Digestive and Kidney Diseases (NIDDK), NIH, Bethesda, Maryland, USA
  • 5Department of Medicine, Division of Endocrinology, Johns Hopkins University, Baltimore Maryland, USA
  • 6University of Chile, Casilla 226-3, Santiago, Chile
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received 27.09.2008

accepted 02.03.2009

23. April 2009 (online)


Prolactinomas are rare tumors in prepubertal children. A prolactinoma in a young child may be due to sequence variants in genes that are known to cause these tumors (MEN1, PRKAR1A, AIP). An 11-year-old boy with a macroprolactinoma was treated with cabergoline and the tumor receded. We studied the patient and his family for genetic causes of this tumor. No mutations were present in the coding sequence of PRKAR1A and AIP. A novel heterozygous substitution (IVS3-7 c>a) was identified in intron 3 of MEN1. We also found an additional PCR amplicon that incorporated the entire intron 3 of the gene (210 bp) in the patient's cDNA. The same amplicon was present with lower intensity in some of the control individuals who were not mutation carriers. Intron 3 harbors an in-frame stop codon and its incorporation is predicted to result in a prematurely terminated protein. We conclude that a novel MEN1 variation was identified in a young boy with prolactinoma and six of his relatives who did not present with prolactinoma or other MEN1 related symptoms. This novel MEN1 variation may be associated with low penetrance of the disease. The IVS3-7 c>a defect is suggested to be pathogenic because it is associated with lower menin levels in the cells of these patients, but its consequences may be mitigated by a variety of factors including changes in transcription and translation of the MEN1 gene.



C. A. Stratakis, MD, DSc 


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