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Departments of Endocrinology (A.F.D., A.Be.) and Molecular Genetics (J.-F.V., V.B.), Centre Hospitalier Universitaire de Liège, University of Liège, 4000 Liège, Belgium; Laboratory of Cancer Genetics (S.K.K., B.T.T., D.C.L.-C.), and Laboratory of Germline Modification and Cytogenetics (S.K.K.), Van Andel Research Institute, Grand Rapids, Michigan 49503; Department of Experimental Medicine (M.-L.J.-R.), University of L’Aquila, and Neuromed, Istituto di Ricovero e Cura a Carattere Scientifico, 86077 Pozzili, Italy; Division of Endocrinology (L.A.N.), University of Brasilia, Brasilia, Brazil 70910-900; Neuroscience Institute (M.A.G., A.Bas.), and TCba Salguero Laboratory (A.O., D.D., A.S.), Faculty of Medicine, University of Buenos Aires, C117AE1 Buenos Aires, Argentina; Department of Endocrinology (A.M.), Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France; Department of Endocrinology (P.E.), Centre Hospitalier Regional, 45032 Orléans, France; Department of Genetics (A.-P.G.-R.), Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université René Descartes-Paris 5 and Institut National de la Santé et de la Recherche Médicale U772, Collège de France, 75908 Paris, France; Department of Clinical Science (G.T.), Endocrine Section, University of Rome La Sapienza, 00100 Rome, Italy; Departments of Endocrinology (G.R.) and Human Genetics (A.Ca., O.S.), Centre Hospitalier Universitaire de Lyon, 69495 Lyon, France; Laboratoire de Biochimie Biologie Moléculaire (A.Bar.), Centre Hospitalier Universitaire Conception, 13385 Marseille, France; Section of Endocrinology (W.D.H.), Department of Internal Medicine, Erasmus Medical Centre, 3015 GD Rotterdam, The Netherlands; Department of Endocrinology (A.P.), Centre Hospitalier Universitaire de Besançon, 25030 Besançon, France; Division of Endocrinology and Metabolism (E.C.), Department of Internal Medicine, University of Turin, 10100 Turin, Italy; Department of Endocrinology (B.E.), Centre Hospitalier Universitaire de Saint Etienne, 42055 Saint Etienne, France; Unit of Endocrinology (P.L.), Centre Hospitalier Régional Universitaire Tours, 37044 Tours Cedex 9, France; Department of Endocrinology (B.G.), Centre Hospitalier Universitaire de Bordeaux, Hôpital Haut Lévéque, 33604 Pessac, France; Department of Endocrinology (O.C.), Centre Hospitalier Universitaire Grenoble, 38043 Grenoble, France; Austral University Hospital (M.I.S., N.G.B.), B1629AHJ Buenos Aires, Argentina; Department of Endocrine and Metabolic Disease (X.B.), Centre Hospitalier d’Université Cochin, 75014 Paris, France; Pirovano General Acute Hospital (G.S.), 1430 Buenos Aires, Argentina; Department of Molecular and Clinical Endocrinology and Oncology (A.Co.), University "Federico II," 80131 Naples, Italy; Department of Internal Medicine and Endocrine Sciences (P.F.), University of Perugia, 06100 Perugia, Italy; Endocrinological Clinic Marc Linquette (J.-L.W.), Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France; Department of Endocrinology and Metabolic Disorders (P.C.), University Hospital Rangueil, 31403 Toulouse Cedex, France; Department of Endocrinology and Metabolic Diseases (J.-L.S.), Centre Hospitalier Universitaire de Nice, 06202 Nice Cedex 3, France; Departments of Internal Medicine and Endocrinology (F.A.), Hôpital du Cluzeau, 87042 Limoges, France; Department of Endocrinology (C.F.M.), Hospital de la Ribera, 46600 Alzira, Valencia, Spain; Department of Endocrinology (F.C.), Ospedale San Luca, Istituto Auxologico Italiano, Instituto di Ricovero e Cura a Carattere Scientifico, 20149 Milan, Italy; Third Department of Medicine (V.H.), First Medical Faculty, Charles University, 128 02 Prague 2, Czech Republic; Division of Endocrinology (D.C.L.-C.), Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil 21949-590; Department of Endocrinology (V.R.), Centre Hospitalier Universitaire de Angers, 49033 Angers, France; and Laboratoire Interactions Cellulaires Neuroendocriniennes (T.B.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 6544, Institut Fédératif Jean Roche, Faculté de Médecine, Université de la Méditerranée, 13284 Marseille Cedex 7, France
Address all correspondence and requests for reprints to: Albert Beckers, M.D., Ph.D., Department of Endocrinology, Centre Hospitalier Universitaire de Liège, University of Liège, Domaine Universitaire du Sart Tilman, 4000 Liège, Belgium. E-mail: albert.beckers{at}chu.ulg.ac.be.
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Abstract |
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Objective: The objective of the study was to assess the frequency of AIP gene mutations in a large cohort of patients with familial isolated pituitary adenoma (FIPA).
Design: This was a multicenter, international, collaborative study.
Setting: The study was conducted in 34 university endocrinology and genetics departments in nine countries.
Patients: Affected members from each FIPA family were studied. Relatives of patients with AIP mutations underwent AIP sequence analysis.
Main Outcome Measures: Presence/absence and description of AIP gene mutations were the main outcome measures.
Intervention: There was no intervention.
Results: Seventy-three FIPA families were identified, with 156 patients with pituitary adenomas; the FIPA cohort was evenly divided between families with homogeneous and heterogeneous tumor expression. Eleven FIPA families had 10 germline AIP mutations. Nine mutations, R16H, G47_R54del, Q142X, E174frameshift, Q217X, Q239X, K241E, R271W, and Q285frameshift, have not been described previously. Tumors were significantly larger (P = 0.0005) and diagnosed at a younger age (P = 0.0006) in AIP mutation-positive vs. mutation-negative subjects. Somatotropinomas predominated among FIPA families with AIP mutations, but mixed GH/prolactin-secreting tumors, prolactinomas, and nonsecreting adenomas were also noted. Approximately 85% of the FIPA cohort and 50% of those with familial somatotropinomas were negative for AIP mutations.
Conclusions: AIP mutations, of which nine new mutations have been described here, occur in approximately 15% of FIPA families. Although pituitary tumors occurring in association with AIP mutations are predominantly somatotropinomas, other tumor types are also seen. Further study of the impact of AIP mutations on protein expression and activity is necessary to elucidate their role in pituitary tumorigenesis in FIPA.
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Introduction |
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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From the original FIPA cohort, 51 families took part in the current study of AIP mutations. In addition, 22 new, previously undescribed FIPA families without MEN1 or CNC were identified and included in the study. Relevant data on demographics and clinical characteristics were collected for each affected member of each family, including age at diagnosis, tumor size, and if available, pituitary hormone immunohistochemistry. Age at diagnosis and mean maximum tumor diameter in the FIPA group overall and for AIP mutation-affected subjects only were calculated as means, medians, 95% confidence intervals, and SD. In families in which a mutation in AIP was noted, genetic analysis for this mutation was offered in other affected and unaffected family members; clinical, hormonal, and radiological (magnetic resonance imaging) assessment of individuals that were positive for an AIP mutation was also offered. The study was conducted in accordance with the guidelines in The Declaration of Helsinki, approved by the Ethics Committee of the University of Liège, and all subjects provided informed written consent in their own language for the genetic analyses performed during the study.
Statistical analyses
Statistical analyses were performed using GraphPad Instat for Macintosh (GraphPad Software, San Diego, CA). The Mann-Whitney test for univariate analyses, with a two-sided P value, compared data from continuous variables (e.g. age at diagnosis and maximum tumor diameter) from subgroups of patients with and without AIP mutations. Sex distribution and the proportions of patients with microadenomas and macroadenomas in the AIP mutation-positive and negative groups were analyzed using the Fisher’s exact test, with a two-sided P value. A P value of <0.05 was considered significant for all analyses.
AIP genetic analysis
Genomic DNA was isolated from blood samples from at least one affected member of each FIPA family. The structure of AIP was based on Ensembl sequences ENST00000279146, ENSG00000110711, and ENSP00000279146. The primers used for the analysis of the AIP exonic and flanking intronic sequences are as reported by Vierimaa et al. (12). Each 25 µl PCR reaction contained 150 ng genomic DNA, 1 µM each primer, 1.5 mM MgCl2, 10 mM Tris-HCl buffer (pH 8.3), 200 µM dNTPs, and 1.25 U FastStart Taq polymerase (Roche, Vilvoorde, Belgium). PCR conditions were 95 C for 10 min, followed by 30 cycles of 30 sec at 95 C, 30 sec at 68 C, and 20 sec at 72 C. PCR products were sequenced using ABI3100 and BigDye Terminator v3.1 technology (Applied Biosystems, Foster City, CA). A total of 100 blood samples from non-FIPA subjects in Belgium and France were analyzed to assess for polymorphisms in the AIP sequence.
Accession numbers
The accession numbers in GenBank for the novel AIP mutations reported in this study are: EF066502 (R271W), EF066503 (E174frameshift), EF066504 (delG47-R54), EF066505 (K241E), EF066506 (Q142X), EF066507 (Q217X), EF066508 (Q239X), EF066509 (Q285frameshift), and EF066510 (R16H).
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Results |
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A total of 156 subjects were identified among 73 families with the FIPA phenotype (see supplemental Table 1, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). Eleven of 73 (15.1%) FIPA families were found to have 10 different germline mutations in the AIP gene (Fig. 1
). Of these, nine AIP mutations in 10 families have not been reported to date. The characteristics of FIPA families that had AIP mutations are detailed in Table 1. There were three novel mutations that led to premature stop codons: Q142X (c.424C>T), Q217X (c.649C>T), and Q239X (c.715C>T). In addition, one three-member family that had a previously described R304X mutation (12) was identified (c.910C>T). Three missense mutations, R16H (c.47G>A), R271W (c.811C>T), and K241E (c.721A>G), were identified in four FIPA families; R271W was found in two two-member families (Table 1). One two-member family had an in-frame G47_R54del (c.138_161del24) mutation. A frameshift deletion, E174frameshift (c.517_521delGAAGA), that led to a stop codon after 21 incorrect amino acids was identified in a family with three affected members. A second frameshift mutation in a two-member family, Q285frameshift (c.854_857delAGGC), was followed by a stop codon after 17 incorrect amino acids.
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Demographic details and the phenotypic patterns of tumors seen are outlined in Tables 2 and 3, respectively. Briefly, families were divided equally (n = 78 each) among homogeneous and heterogeneous FIPA patterns; two-member homogeneous prolactinoma (n = 18) and somatotropinoma (n = 14) families were the most frequent. All but one heterogeneous FIPA family had at least one member with a prolactinoma or a somatotropinoma. Mean age at diagnosis was significantly lower in subjects with AIP mutations (n = 26 subjects) as compared with those without AIP mutations (n = 130 subjects) (25.7 ± 11.3 vs. 38.8 ± 16.8 yr, respectively; P = 0.0006). Mean maximum tumor diameter was significantly larger in the group with AIP mutations (24.6 ± 10.7 mm) than those without (14.5 ± 10.1 mm; P = 0.0005). Although the proportion of patients with macroadenomas was higher in the AIP mutation-positive group (88.5%) as compared with the AIP mutation-negative group (71.2%), this difference did not reach statistical significance.
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Family members of subjects with pituitary adenomas and AIP mutations were contacted whenever possible and underwent genetic screening. Subjects that were positive for an AIP mutation were offered clinical assessment and hormonal screening. A total of 45 apparently unaffected relatives were screened, and nine individuals (mean age 39.7 yr; range 16–71) from five different families were found to be positive for mutations in AIP. These asymptomatic subjects did not have signs or symptoms suggestive of pituitary tumors, while hormonal and radiological screening was unremarkable.
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Discussion |
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Vierimaa et al. (12) undertook an extensive and detailed study of multiple genes to assess linkage to pituitary adenomas occurring in a familial setting, finally identifying AIP as being associated with pituitary adenomas in large, well-described kindreds in Finland. In that study an AIP mutation was identified in one family from Italy, but two other families with IFS from Germany and Turkey had normal AIP sequences (12). Our data from screening a large, diverse population indicate that AIP mutations occur in about 15% of families in the FIPA cohort. The majority of FIPA families had normal germline AIP sequences, even those with three or four affected subjects. In particular, of the 16 FIPA families with homogeneous presentation of acromegaly (IFS), half were negative for AIP mutations, indicating that this gene does not readily explain IFS in its entirety. Other, as yet unidentified, genetic mutations may be involved in producing the FIPA clinical phenotype. The evidence to date suggests that mutations in AIP may be linked to the expression of a variety of tumor types. Although somatotropinomas predominate among FIPA families with AIP mutations, both pure GH and mixed GH-prolactin secretion and immunohistochemical staining occur commonly, even within the same family. Heterogeneous expression of tumors in FIPA tumor, including prolactinomas or nonsecreting adenomas, can occur in association with AIP mutations. The FIPA cohort contained few patients with less common pituitary tumors such as Cushing’s disease and only one patient with a TSH-secreting adenoma; these were negative for AIP mutations. Therefore, it remains to be seen whether AIP mutations can also occur in families with Cushing’s disease or TSH-secreting adenomas.
A Q14X mutation was the one most frequently seen in the Finnish patients studied, and both familial and sporadic cases were associated with this germline mutation; tumor analysis indicated loss of heterozygosity at the AIP locus (12). One other mutation, IVS3–1G>A, was reported in a sporadic case of acromegaly. In the current study these mutations were not identified in our international series of FIPA families. This, allied with the recent report of the absence of these mutations in sporadic pituitary tumor patients treated in the United States, suggests that these mutations may be characteristic of the Finnish population (14). This would not be unusual in terms of clinical genetics because Finland is known to be relatively genetically homogeneous and subject to founder effects (15). The role of extensive genealogic analysis such as that undertaken by Vierimaa et al. (12) to identify distant links among various affected families is important. We describe an Italian FIPA family with an R304X mutation (c.910C>T), the same mutation reported in an apparently unrelated family elsewhere in Italy (12). Further studies may highlight whether specific patterns of AIP mutations occur among specific geographical or cultural groups.
The impact of reported mutations in AIP on protein expression and function remains to be determined. Data on the structural components of AIP from in vitro studies provide some indicators in that regard. AIP is a protein of 330 amino acids in length, and contains conserved domains that include three tetratricopeptide repeat (TPR) domains and a FK506 binding protein-type peptidyl-prolyl cis-trans isomerase (FKBP-PPI) domain that is analogous to a related domain found in immunophilin proteins. Although the function of the FKBP-PPI domain remains to be determined fully, the importance of the "carboxy half" of AIP (residues 154–330) has been well established (16). Mutation studies of the third TPR domain have revealed that it is necessary for interactions with both heat shock protein 90 (hsp90) and the aryl hydrocarbon receptor (AhR) (17). Point mutations of the third TPR domain in murine AIP, including Y268A, G272D, G272E, A284T, and F288A, lead to an AIP that cannot coimmunoprecipitate hsp90; of these, Y268A and G272D cannot coimmunoprecipitate AhR (18). A further mutation, K266A, also abrogated hsp90 binding but retained AhR binding, albeit at a decreased level (19). Other studies that removed the last 32 amino acids from the C-terminal of AIP also prevented hsp90 binding, while the removal of the last 17 amino acids at the C-terminal led to rapid AIP turnover within COS-1 cells (20). Alanine replacement of any of the final four amino acids or deletion of the final five amino acids at the C terminus of AIP prevents AhR binding (19).
In families with mutations that led directly to stop codons (Q142X, Q217X, Q239X, and R304X), the mutated gene would not encode the third TPR domain, the carboxy terminal amino acids, or both correctly (see supplemental Fig. 1, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). Two other frameshift mutations (Q285fs and E174fs) also led to premature stop codons 17 and 21 amino acids downstream, respectively, and the loss of the sequences coding for the hsp90 and AhR interaction sites on AIP. The G47_R54del mutation, which read in-frame thereafter, would be expected to delete a series of amino acids within the FKBP-PPI domain, which could interfere with the enzymatic function of this region. In FIPA families with missense mutations of AIP, the functional impact is somewhat more difficult to predict. R271W, K241E, and R16H were not found in 100 non-FIPA individuals screened for AIP polymorphisms. Two unrelated FIPA families had an R271W mutation in AIP. This arginine is highly conserved across species, including the mouse, and forms part of the critical third TPR domain. As noted previously, mutation studies in this region in the mouse are known to abrogate hsp90 or AhR binding, or both (17). Given the sequence identity between the human being and mouse in this important region, it appears reasonable to suggest that R271W could interfere with the interaction of AIP and hsp90/AhR in these subjects. Both K241 and R16 are conserved amino acids across a variety of species; however, the impact of such mutations on the structural and functional status of AIP remains to be determined.
In conclusion, the current study shows that AIP mutations occur in 15% of families with the FIPA phenotype. AIP mutations that may abrogate expression or function of AIP protein could impact subsequent AhR responses to cellular and environmental signals, although AIP modulates a variety of other cellular signals (e.g. phosphodiesterases, cAMP) that may be involved in tumorigenesis. Experimental studies to assess AIP protein expression, receptor interactions, and xenobiotic responses will be useful in determining the precise effect on pituitary tumorigenesis of the multiple AIP mutations now identified.
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Acknowledgments |
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Footnotes |
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The sequence data reported in this study have the following GenBank database accession numbers: EF066502, EF066503, EF066504, EF066505, EF066506, EF066507, EF066508, EF066509, and EF066510.
Disclosure Statement: The authors have nothing to disclose.
First Published Online January 23, 2007
Abbreviations: AhR, Aryl hydrocarbon receptor; AIP, AhR-interacting protein; CNC, Carney complex; FIPA, familial isolated pituitary adenoma; FKBP-PPI, FK506-type binding protein type peptidyl-prolyl cis-trans isomerase; hsp90, heat shock protein 90; IFS, isolated familial somatotropinoma; MEN1, multiple endocrine neoplasia type 1; PRKAR1A, R1a regulatory subunit of protein kinase A; TPR, tetratricopeptide repeat.
Received November 15, 2006.
Accepted January 12, 2007.
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References |
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mutations in somatotroph adenomas. J Clin Endocrinol Metab 83:1604–1610 chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340:692–696[CrossRef][Medline]This article has been cited by other articles:
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