A Novel C-terminal Nonsense Mutation, Q315X, of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in a Japanese Fam
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A Novel C-terminal Nonsense Mutation, Q315X, of the Aryl Hydrocarbon Receptor-Interacting Protein Gene in a Japanese Familial Isolated Pituitary Adenoma Family Takeo Iwata & Shozo Yamada & Junko Ito & Naoko Inoshita & Noriko Mizusawa & Shinji Ono & Katsuhiko Yoshimoto
# Springer Science+Business Media New York 2014
Abstract Although the cause of familial isolated pituitary adenoma (FIPA) remains unknown in many cases, germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in approximately 20 % of families with FIPA. We investigated the AIP gene mutation by a standard sequencing method in 12 members of a Japanese two-generation FIPA family, which includes 3 patients with early-onset acromegaly. Multiplex ligation-dependent probe amplification analysis in a tumor sample was attempted to examine the loss of heterozygosity (LOH) in the locus. The effect of the detected mutation on cell proliferation was investigated. A germline mutation of c.943C>T (p.Q315X) generating an AIP protein with the C-terminal end deleted was found in the FIPA family. Biallelic inactivation of AIP by a combination of the germline mutation and LOH at 11q13 was confirmed in the tumor. The nonsense mutation disrupted the ability to inhibit cell proliferation. We conclude that p.Q315X mutation in the AIP gene is a pathogenic variant and the Cterminal region of AIP plays an important role in the predisposition to pituitary adenomas. T. Iwata : N. Mizusawa : S. Ono : K. Yoshimoto (*) Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 3-18-15, Tokushima City 770-8504, Japan e-mail: [email protected] S. Yamada Department of Hypothalamic and Pituitary Surgery, Toranomon Hospital, Toranomon 2-2-2, Minato-ku Tokyo 105-8470, Japan J. Ito Department of Pediatrics, Toranomon Hospital, Toranomon 2-2-2, Minato-ku Tokyo 105-8470, Japan N. Inoshita Department of Pathology, Toranomon Hospital, Toranomon 2-2-2, Minato-ku Tokyo 105-8470, Japan
Keywords Familial isolated pituitary adenoma . Acromegaly . Aryl hydrocarbon receptor-interacting protein . Loss of heterozygosity
Introduction Pituitary adenomas that are relatively common in the general population are usually sporadic; however, familial adenomas have been identified in 3–5 % of all cases [1, 2]. Multiple endocrine neoplasia type 1 (MEN1) and Carney complex are well-characterized familial syndromes forming multiple endocrine neoplasia including anterior pituitary tumors. In MEN1, germline mutations in the MEN1 gene have been found in most patients [3, 4]. In 60 % of patients with Carney complex, germline mutations of the PRKAR1A gene encoding the R1α regulatory subunit of cAMP-dependent protein kinase A on 17q22-24 were detected [5]. Familial isolated pituitary adenoma (FIPA) is defined as the occurrence of two or more related members of the pituitary adenomas outside of the setting of MEN1 or Carney complex in a kindred. In FIPA, pituitary adenomas are presented homogeneous
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