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Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas

¹ INSERM, U567, 75 Paris, France, ² Institut Cochin, Université Paris Descartes, CNRS (UMR8104), 75 Paris, France, ³ Faculté de Médecine René Descartes, Université Paris 5, Paris F-75014, France, ⁴ Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Unité d’Oncogénétique, 75 Paris, France, ⁵ Département de Génétique, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France, ⁶ Département d’Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France, ⁷ Département d’Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France, ⁸ Faculté de Médicine de Bicêtre, Université Paris Sud, 94 Le Kremlin Bicêtre, France, ⁹ Département d’Endocrinologie, Assistance Publique Hôpitaux de Paris, Hôpital Ambroise Paré, 92 Boulogne, France and ¹⁰ Faculté de Médecine Paris-Ile de France Ouest, Université de Versailles Saint-Quentin-en-Yvelines, 10 Garches, France

(Correspondence should be addressed to M-L Raffin-Sanson who is now at Unité d’Endocrinologie, Hôpital Ambroise Paré, 92240 Boulogne, France; Email: marie-laure.raffin-sanson{at}apr.aphp.fr)

Objective: Germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have recently been described in three families with GH or prolactin-secreting tumors, as well as in a few patients with apparently sporadic somatotropinomas. The aim of the study was to determine the prevalence of AIP mutations in a large cohort of patients with apparently sporadic GH-secreting tumors.

Design: One hundred and fifty-four patients were included in a prospective cohort designed to study the genetic predisposition to GH-secreting tumors together with 270 controls.

Methods: In all these subjects, the entire coding sequence of the AIP gene was screened for germline mutations.

Results: AIP mutations were detected in 5 out of 154 patients (3%): nonsense mutations in exon 4 (p.Lys201X; n = 2) and in exon 6 (p.Arg304X), one deletion in exon 3 (c.404delA; pHis135LeufsX21), and one mutation affecting the splice acceptor site of exon 4 (c.469-2 A > G). The five patients with an AIP mutation were significantly younger (mean age ± S.D.: 25 ± 10 vs 43 ± 14 years, P = 0.005) and three of them presented with gigantism. One missense mutation (p.Arg304Gln) was found in a single patient that was absent in all controls.

Conclusions: Germline mutations of the AIP gene were found in a small proportion of patients with sporadic pituitary somatotropinomas. This study shows that age and gigantism are simple clinical features which can help to select patients for mutation screening. It also supports the role of AIP in pituitary tumorigenesis.

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