Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma.
BACKGROUND
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.


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


METHODS
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.
Toledo
Rodrigo A
RA
Unidade de Endocrinologia Genética, Faculdade de Medicina, Universidade de São Paulo, Av Dr Arnaldo 455-5 andar, São Paulo-SP, Brazil 01246-903. toldo@usp.br
Lourenço
Delmar M
DM
Liberman
Bernardo
B
Cunha-Neto
Malebranche B C
MB
Cavalcanti
Maria G
MG
Moyses
Cinthia B
CB
Toledo
Sergio P A
SP
Dahia
Patricia L M
PL
D000172:Acromegaly / Q000235:genetics; D000328:Adult; D002675:Child, Preschool; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010911:Pituitary Neoplasms / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D004247:DNA