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Germline Mutation in the Aryl Hydrocarbon Receptor Interacting Protein Gene in Familial Somatotropinoma

Unidade de Endocrinologia Genética LIM-25, Endocrinologia (R.A.T., D.M.L., M.G.C., C.B.M., S.P.A.T.) and Neuroendocrine Unit (M.B.C.C.-N.), Division of Neurosurgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brazil; Hospital Brigadeiro (B.L.), São Paulo 04107-030, Brazil; and Departments of Medicine and Cellular and Structural Biology (P.L.M.D.), San Antonio Cancer Institute, University of Texas Health Science Center, San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Sergio Toledo, Unidade de Endocrinologia Genética, Av Dr Arnaldo 455-5° andar, São Paulo-SP, Brazil 01246-903. E-mail: toldo{at}usp.br; or Patricia Dahia, Department of Medicine, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, MC 7880, San Antonio, Texas 78229. E-mail: dahia{at}uthscsa.edu.

Context: Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were associated with familial pituitary adenoma predisposition.

Objective: The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family.

Settings: The study was conducted at a nonprofit academic center and medical centers.

Patients: Eighteen members of a Brazilian family with acromegaly were studied.

Results: A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls.

Conclusions: We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.

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