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Germline Mutation in the Aryl Hydrocarbon Receptor Interacting Protein Gene in Familial Somatotropinoma

Unidade de Endocrinologia Genética LIM-25, Endocrinologia (R.A.T., D.M.L., M.G.C., C.B.M., S.P.A.T.) and Neuroendocrine Unit (M.B.C.C.-N.), Division of Neurosurgery, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brazil; Hospital Brigadeiro (B.L.), São Paulo 04107-030, Brazil; and Departments of Medicine and Cellular and Structural Biology (P.L.M.D.), San Antonio Cancer Institute, University of Texas Health Science Center, San Antonio, Texas 78229

Address all correspondence and requests for reprints to: Sergio Toledo, Unidade de Endocrinologia Genética, Av Dr Arnaldo 455-5° andar, São Paulo-SP, Brazil 01246-903. E-mail: toldo{at}usp.br; or Patricia Dahia, Department of Medicine, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, MC 7880, San Antonio, Texas 78229. E-mail: dahia{at}uthscsa.edu.

	Abstract

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Context: Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were associated with familial pituitary adenoma predisposition.

Objective: The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family.

Settings: The study was conducted at a nonprofit academic center and medical centers.

Patients: Eighteen members of a Brazilian family with acromegaly were studied.

Results: A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls.

Conclusions: We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.

	Introduction

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ACROMEGALY IS A syndrome of hormone excess characterized by high serum levels of GH mostly due to a GH-producing pituitary adenoma (1). Most cases are sporadic; however, familial acromegaly may also occur in association with multiple endocrine neoplasia type 1 (MEN1), Carney complex, and also with various hereditary conditions known as pituitary adenoma predisposition (PAP), familial isolated pituitary adenoma (FIPA), and isolated familial somatotropinoma (IFS) (2, 3). IFS is defined by the finding of at least two patients with acromegaly/gigantism in a family not associated with MEN1 or Carney complex and accounts for approximately 18% of FIPAs (4). Typically, both IFS and FIPA patients are younger at diagnosis than their sporadic counterparts; their tumors tend to be larger (88% of IFS cases are macroadenomas) and, in IFS, have a more aggressive course. IFS, and possibly also FIPA, appear to be inherited as an autosomal dominant trait with incomplete penetrance (2, 5). The IFS locus has been mapped to 11q13; however, the molecular etiology of IFS has remained elusive (6).

Recently, germline mutations of the aryl hydrocarbon receptor interacting protein (AIP) gene, also known as ARA9 or XAP2, were identified in familial clusters with PAP (3). These mutations were accompanied by loss of heterozygosity of the remaining allele in the tumor tissue, indicative of a tumor suppressor role for the AIP gene. In the above-referred study, one of three IFS kindreds screened was found to carry a germline AIP mutation (3). There have now been additional reports of AIP mutations in both familial (FIPA and IFS) and sporadic acromegaly, which provide the framework for defining genotype-phenotype correlations in pituitary adenoma syndromes (7, 8, 9). From these recent data, AIP has been suggested to act as a low-penetrance gene in familial pituitary clusters. We report here the identification of a novel AIP mutation in a family with acromegaly, which further validates the role of this gene in human pituitary tumor predisposition, and discuss the current status of the genetics of familial pituitary tumors in light of these new findings.

	Patients and Methods

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We have followed two siblings with acromegaly (III-15, III-16) for the past 24 yr at the Hospital das Clínicas, University of São Paulo School of Medicine. Partial results from this family have been described elsewhere (10). Briefly, their age at diagnosis was 24 and 29 yr with reported onset of symptoms at 21 and 17 yr old, respectively, and both presented with invasive macroadenomas, as revealed by pituitary imaging studies (Table 1). Moreover, no mutations were detected in the GHRH-R, MEN1, PRKAR1A, GNAS1, or GNAI2 genes in these patients (10, 11).

View larger version (41K): [in this window] [in a new window]   FIG. 1. A, Pedigree of a Brazilian family with acromegaly. Arrow points to the proband. B, AIP genetic analysis: Chromatogram traces showing the heterozygous A to C nucleotide change (arrow; Y268X) in exon 6 of the AIP gene in affected siblings. The Y268X mutation results in a premature TAA-stop signal, leading to a predicted protein lacking its final 63 amino acids. Forward and reverse traces are shown on top and bottom panels, respectively. wt, Wild-type sequence.

	Results

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AIP gene analysis

Mutation analysis revealed a nucleotide substitution A>C at position 804 in exon 6 of the AIP gene coding sequence in four family members (III-15, III-16, III-17 and IV-33, Fig. 1B). This variant results in a premature TAA-stop signal at codon 268 (Y268X), leading to a predicted protein lacking the final 63 amino acids (GenBank accession no. EF437945). Missense mutations of this codon have been detected in other FIPA families (7). The Y268X mutation is located at the beginning of the third tetratricopeptide repeat domain, shown to be involved in protein-protein interactions that are critical to AIP function (13). The 268 codon and deleted region span the interacting domains for the aryl hydrocarbon receptor and heat-shock protein 90 (13, 14). However, one possibility is that the mutant transcript is unstable and therefore subject to degradation by the nonsense-mediated decay mechanism with no resulting protein product (15). Thus, the Y268X mutation is expected to alter AIP activity, although the precise mechanism for pituitary cell growth in response to this inactivating mutation remains to be clarified.

Individual III-17 was a 41-yr-old male with no clinical signs of disease. To further establish the extent of disease penetrance, a detailed biochemical and imaging analysis was carried out in this individual (Table 1). Both baseline and postoral glucose tolerance test GH was 0.1 ng/ml and less than 1 ng/ml, respectively (normal < 4.4 ng/ml), and IGF was 154 ng/ml (normal 101–267 ng/ml). Serum values of prolactin (PRL), ACTH, TSH, LH, FSH, and cortisol were normal (not shown). Magnetic resonance imaging (MRI) revealed a 3-mm hypodense pituitary nodule with slight deviation of the pituitary infundibulum and no extrasellar extension. Visual fields were normal. His 3-yr-old asymptomatic child (75th percentile for height and weight) was also found to carry this mutation. No other Y268X mutation carrier was identified among the remaining 14 relatives.

To exclude that Y268X was an unreported polymorphism, we analyzed an additional 184 chromosomes from 92 healthy controls and did not detect the Y268X allele in these samples.

	Discussion

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Until recently the molecular pathogenesis of IFS and sporadic pituitary tumors remained elusive, although loss of heterozygosity at the 11q13 locus has been described in both sporadic and familial pituitary adenomas (6). The MEN1 gene, located at this region, was ruled out in these cases, suggesting that another tumor suppressor gene at the 11q13 locus is involved in pituitary tumorigenesis (6, 10, 16, 17). The AIP gene, which maps to the 11q13 region, was recently associated with PAP (3). Two other recent reports of AIP gene screening in families with pituitary tumors have started to define genotype-phenotype correlations (7, 8). Currently a total of 14 germline AIP mutations, including the novel mutation identified in our study, have been reported in familial pituitary adenoma settings. Of note, mutation rates were higher in IFS families, compared with heterogeneous FIPA families, in which different tumor types are present in affected individuals (50% vs. 10%, respectively). Among the latter, GH- and PRL-secreting adenomas and also nonsecreting tumors appear to predominate in mutation-positive families (7).

Our present report of a novel germline AIP mutation, Y268X, in a Brazilian family further validates the involvement of the AIP gene in familial acromegaly/pituitary adenoma syndrome. Importantly, the detection of the AIP mutation in a 41-yr-old individual with a nonsecreting pituitary microadenoma, in contrast with the early-onset and aggressive disease of his two affected siblings, is consistent with an emerging profile whereby AIP mutations have incomplete penetrance and associate with pituitary tumors of lineages other than somatotrophs (3, 7). These data support the classification of this kindred as either IFS or FIPA, reflecting the challenges in the nomenclature used to define pituitary predisposition at the clinical level. Future classification algorithms may be called for in the near future and could, for example, be guided primarily by the genetic defect. In this family, unidentified factor(s), either genetic or epigenetic, could be acting to diminish or delay pituitary tumor growth and/or secretion in this mutation carrier. Accordingly, the inheritance pattern and mutation rates observed in IFS as well as PAP and FIPA suggest the existence of additional susceptibility genes and also other modulating factors in somatotropinoma tumorigenesis (3, 7, 8). Identification of additional putative loci for somatotropinoma susceptibility at 2p16–12 and 13q14 supports that view (12, 18). Interestingly, we were able to exclude sequence changes in the somatostatin receptor (SSTR) 2 and 5 (SSTR2 and SSTR5) genes as candidate modulating factors of the phenotypic diversity in this family (data not shown). These genes are known to be involved in somatostatin-mediated GH suppression and SSTR5 variants have been recently described in association with increased GH and IGF levels of patients with sporadic acromegaly (19) and have not been previously examined in familial acromegaly.

The role of AIP in sporadic acromegaly and pituitary tumors of other lineages is also starting to be addressed. Germline AIP mutations were reported in three of 45 patients (6%) with sporadic acromegaly in Finland (3), one of 156 from various European countries (20) and one of 40 from Japan (8), but none of 35 cases in the United States tested specifically for the three original AIP mutations (9). Our own preliminary data suggest that the contribution of AIP to sporadic acromegaly in Brazilian patients may also be limited (no mutation found in 20 cases, data not shown). We were also able to exclude mutations in the AIP coding sequence in a mother-daughter pair with ACTH-secreting pituitary adenomas (Toledo, R. A., and P. L. M. Dahia, unpublished data). This is in agreement with data from Daly et al. (7) and suggests that mutation prevalence may be related to not only population genetic backgrounds but also specific pituitary lineages. The continuing analysis of multiethnic cohorts of pituitary adenomas of various lineages will precisely define AIP’s role in pituitary tumorigenesis.

Identification of AIP mutations increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. The mechanisms of tumor formation due to disruption of this gene and the basis for the variable clinical phenotype are still unknown. Currently due to the scattered nature of the mutations, it is not possible to establish a precise relationship between type or site of mutations and clinical disease. In the near future, however, it is reasonable to suppose that AIP may develop into a screening tool relevant for genetic counseling and clinical surveillance of families with pituitary tumors.

	Footnotes

 
This work was supported by the São Paulo State Research Foundation (FAPESP) Grant 02/09860-8. R.A.T. and D.M.L. are recipients of Fundação Faculdade de Medicina fellowships. S.P.A.T. is partially supported by Brazilian National Research Council (CNPq). P.L.M.D. is a recipient of a South Texas Health Research Center Junior Faculty Award, an Executive Research Committee New Investigator Award, and a General Clinical Research Center Award.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 6, 2007

Abbreviations: AIP, Aryl hydrocarbon receptor interacting protein; FIPA, familial isolated pituitary adenoma; IFS, isolated familial somatotropinoma; MEN1, multiple endocrine neoplasia type 1; MRI, magnetic resonance imaging; PAP, pituitary adenoma predisposition; PRL, prolactin; SSTR, somatostatin receptor.

Received November 1, 2006.

Accepted February 27, 2007.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Toledo, R. A. Articles by Dahia, P. L. M. Search for Related Content PubMed PubMed Citation Articles by Toledo, R. A. Articles by Dahia, P. L. M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM Protein UniGene Compound via MeSH Substance via MeSH Related Collections Diabetes and Insulin Endocrine Oncology