PURPOSE: Acromegaly usually occurs as a sporadic disease, but it may be a part of familial pituitary tumor syndromes in rare cases. Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated with a predisposition to familial isolated pituitary adenoma. The aim of the present study was to evaluate the AIP gene in a patient with gigantism and in her relatives. METHODS: Direct sequencing of AIP gene was performed in fourteen members of the family, spanning among three generations. RESULTS: The index case was an 18-year-old woman with gigantism due to an invasive GH-secreting pituitary adenoma and a concomitant tall-cell variant of papillary thyroid carcinoma. A novel germline mutation in the AIP gene (c.685C>T, p.Q229X) was identified in the proband and in two members of her family, who did not present clinical features of acromegaly or other pituitary disorders. Eleven subjects had no mutation in the AIP gene. Two members of the family with clinical features of acromegaly refused either the genetic or the biochemical evaluation. The Q229X mutation was predicted to generate a truncated AIP protein, lacking the last two tetratricopeptide repeat domains and the final C-terminal α-7 helix. CONCLUSIONS: We identified a new AIP germline mutation predicted to produce a truncated AIP protein, lacking its biological properties due to the disruption of the C-terminus binding sites for both the chaperones and the client proteins of AIP.
PURPOSE:Acromegaly usually occurs as a sporadic disease, but it may be a part of familial pituitary tumor syndromes in rare cases. Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene have been associated with a predisposition to familial isolated pituitary adenoma. The aim of the present study was to evaluate the AIP gene in a patient with gigantism and in her relatives. METHODS: Direct sequencing of AIP gene was performed in fourteen members of the family, spanning among three generations. RESULTS: The index case was an 18-year-old woman with gigantism due to an invasive GH-secreting pituitary adenoma and a concomitant tall-cell variant of papillary thyroid carcinoma. A novel germline mutation in the AIP gene (c.685C>T, p.Q229X) was identified in the proband and in two members of her family, who did not present clinical features of acromegaly or other pituitary disorders. Eleven subjects had no mutation in the AIP gene. Two members of the family with clinical features of acromegaly refused either the genetic or the biochemical evaluation. The Q229X mutation was predicted to generate a truncated AIP protein, lacking the last two tetratricopeptide repeat domains and the final C-terminal α-7 helix. CONCLUSIONS: We identified a new AIP germline mutation predicted to produce a truncated AIP protein, lacking its biological properties due to the disruption of the C-terminus binding sites for both the chaperones and the client proteins of AIP.
Authors: A F Daly; M-L Jaffrain-Rea; A Ciccarelli; H Valdes-Socin; V Rohmer; G Tamburrano; C Borson-Chazot; B Estour; E Ciccarelli; T Brue; P Ferolla; P Emy; A Colao; E De Menis; P Lecomte; F Penfornis; B Delemer; J Bertherat; J L Wémeau; W De Herder; F Archambeaud; A Stevenaert; A Calender; A Murat; F Cavagnini; A Beckers Journal: J Clin Endocrinol Metab Date: 2006-06-20 Impact factor: 5.958
Authors: Fred Williams; Steven Hunter; Lisa Bradley; Harvinder S Chahal; Helen L Storr; Scott A Akker; Ajith V Kumar; Stephen M Orme; Jane Evanson; Noina Abid; Patrick J Morrison; Márta Korbonits; A Brew Atkinson Journal: J Clin Endocrinol Metab Date: 2013-01-01 Impact factor: 5.958
Authors: Marianthi Georgitsi; Anniina Raitila; Auli Karhu; Karoliina Tuppurainen; Markus J Mäkinen; Outi Vierimaa; Ralf Paschke; Wolfgang Saeger; Rob B van der Luijt; Timo Sane; Mercedes Robledo; Ernesto De Menis; Robert J Weil; Anna Wasik; Grzegorz Zielinski; Olga Lucewicz; Jan Lubinski; Virpi Launonen; Pia Vahteristo; Lauri A Aaltonen Journal: Proc Natl Acad Sci U S A Date: 2007-02-28 Impact factor: 11.205
Authors: I Tuominen; E Heliövaara; A Raitila; M-R Rautiainen; M Mehine; R Katainen; I Donner; V Aittomäki; H J Lehtonen; M Ahlsten; L Kivipelto; C Schalin-Jäntti; J Arola; S Hautaniemi; A Karhu Journal: Oncogene Date: 2014-03-24 Impact factor: 9.867