title: Mutation analysis of inhibitory guanine nucleotide binding protein alpha (GNAI) loci in young and familial pituitary adenomas.
abstract: Pituitary adenomas are neoplasms of the anterior pituitary lobe and account for 15-20% of all intracranial tumors. Although most pituitary tumors are benign they can cause severe symptoms related to tumor size as well as hypopituitarism and/or hypersecretion of one or more pituitary hormones. Most pituitary adenomas are sporadic, but it has been estimated that 5% of patients have a familial background. Germline mutations of the tumor suppressor gene aryl hydrocarbon receptor-interacting protein (AIP) predispose to hereditary pituitary neoplasia. Recently, it has been demonstrated that AIP mutations predispose to pituitary tumorigenesis through defective inhibitory GTP binding protein (Gαi) signaling. This finding prompted us to examine whether germline loss-of-function mutations in inhibitory guanine nucleotide (GTP) binding protein alpha (GNAI) loci are involved in genetic predisposition of pituitary tumors. To our knowledge, this is the first time GNAI genes are sequenced in order to examine the occurrence of inactivating germline mutations. Thus far, only somatic gain-of-function hot-spot mutations have been studied in these loci. Here, we have analyzed the coding regions of GNAI1, GNAI2, and GNAI3 in a set of young sporadic somatotropinoma patients (n = 32; mean age of diagnosis 32 years) and familial index cases (n = 14), thus in patients with a disease phenotype similar to that observed in AIP mutation carriers. In addition, expression of Gαi proteins was studied in human growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH)-secreting and non-functional pituitary tumors. No pathogenic germline mutations affecting the Gαi proteins were detected. The result suggests that loss-of-function mutations of GNAI loci are rare or nonexistent in familial pituitary adenomas.
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Hande
authors.initials: H
authors.lastname: Demir
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Iikki
authors.initials: I
authors.lastname: Donner
authors.affiliation: Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Kivipelto
authors.affiliation: Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kuismin
authors.affiliation: Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Schalin-Jäntti
authors.affiliation: Department of Internal Medicine, General Hospital, Montebelluna, Treviso, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: De Menis
authors.affiliation: Department of Medical Genetics, Genome-Scale Biology Research Program, Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
mesh_terms: D000293:Adolescent; D000324:Adrenocorticotropic Hormone / Q000235:genetics / Q000378:metabolism; D000328:Adult; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics* / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D049912:Growth Hormone-Secreting Pituitary Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013006:Growth Hormone; C584114:GNAI1 protein, human; C498015:GNAI2 protein, human; C498819:GNAI3 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go