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Submitted on November 1, 2006
Accepted on February 27, 2007
Unidade de Endocrinologia Genética LIM-25, Endocrinologia and Neuroendocrine Unit, Division of Neurosurgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, SP, Brazil; Hospital Brigadeiro, São Paulo, SP, Brazil; Depts. of Medicine and Cellular & Structural Biology, San Antonio Cancer Institute, University of Texas Health Science Center, San Antonio-TX
* To whom correspondence should be addressed. E-mail: toldo{at}usp.br.
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 adenomas predisposition (PAP).
Objective: To investigate the status of AIP in a pituitary tumor predisposition family.
Settings: Non-profit 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-year old sibling with a microadenoma but no clinical features of disease and his 3 year-old son. No changes were found in 14 unaffected at-risk relatives or in 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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