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Study of the Multiple Endocrine Neoplasia Type 1, Growth Hormone-Releasing Hormone Receptor, Gs, and Gi2 Genes in Isolated Familial Acromegaly¹

Endocrine Genetics Unit (LIM-25) and Hormone and Molecular Genetics Laboratory, Endocrinology Section, Department of Medicine, University of Sao Paulo School of Medicine (B.H.J., V.S.L., R.R.B., N.A., S.P.A.T.), Sao Paulo SP 01246-903, Brazil; Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health (S.K.A., S.J.M.), Bethesda, Maryland 20892; and Division of Endocrinology, Departments of Medicine and Pediatrics, The Johns Hopkins University School of Medicine (R.S., M.A.L.), Baltimore, Maryland 21287

Address all correspondence and requests for reprints to: Dr. Beatriz H. Jorge, Endocrine Genetics Unit, University of Sao Paulo School of Medicine, Avenue Dr. Arnaldo, 455 5th Floor, Sao Paulo SP 01246-903, Brazil. E-mail: beatrizjorge{at}hotmail.com

Familial acromegaly may occur as an isolated pituitary disorder or as a feature of hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN1) or the Carney complex. Herein, we characterized a newly identified kindred with isolated acromegaly and searched for germline mutation in genes that have been associated with endocrine tumors [i.e. MEN1, Gs (GNAS1), and Gi2 (GNAI2)], as well as the GHRH receptor (GHRH-R) gene. Genomic DNA was used to amplify exons 2–10 of MEN1, followed by dideoxy fingerprinting mutation analysis and direct sequencing. The GHRH-R gene was analyzed via direct sequencing of PCR-amplified fragments representing the coding exons and intron-exon junctions. To exclude mutation at hot spot areas of GNAS1 and GNAI2, exons 8 and 9 of GNAS1 and exons 5 and 6 of GNAI2 were amplified and screened for mutation via denaturing gradient gel electrophoresis. No mutations were detected in any of the four genes. The present data extend prior reports of the absence of mutation in MEN1, GHRH-R, and GNAS1 and describe the first family with isolated acromegaly in which germline mutation in GNAI2 has been searched.

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