CONTEXT: The molecular pathogenesis of primary hyperparathyroidism is still 
largely unknown. The aryl hydrocarbon receptor interacting protein (AIP) gene 
has a major role in the pathogenesis of familial isolated pituitary adenoma.
OBJECTIVE: We evaluated the involvement of the AIP gene in sporadic parathyroid 
adenomas.
PATIENTS AND DESIGN: We performed direct sequencing and multiplex 
ligation-dependent probe amplification analyses of the AIP gene in a large 
series of sporadic parathyroid adenomas. Loss of heterozygosity (LOH) at the AIP 
locus was studied, and aryl hydrocarbon receptor interacting protein 
immunostaining was also performed. In addition, alterations in the MEN1 gene 
were studied.
RESULTS: A somatic AIP mutation, substitution of arginine with glutamine at 
codon 304 (R304Q), was identified in 2 of 132 tumors. The mutation was germline 
in both cases despite the nonfamilial presentation. Heterozygous AIP large 
deletions were detected in 29 cases including 1 of the 2 mutated tumors, 
confirming a biallelic inactivation of the AIP gene. The AIP-mutated tumor with 
LOH showed decreased AIP immunostaining compared with normal parathyroid. LOH at 
the MEN1 locus, which often shared LOH at the AIP locus, was found in one third 
of tumors. Somatic MEN1 mutations were found in the 1 of the 2 AIP-mutated 
tumors and in 22 parathyroid adenomas. In addition, multiplex ligation-dependent 
probe amplification analysis revealed 1 large deletion of the MEN1 gene in 1 
patient.
CONCLUSIONS: The AIP gene is rarely involved in parathyroid adenomas, but the 
germline nature of the mutations suggests that it might predispose to primary 
hyperparathyroidism. MEN1 gene alterations occur in a substantial proportion of 
sporadic parathyroid adenomas.