Familial acromegaly – the role of the AIP gene

M Gueorguiev; F Lolli; JP Chapple; R Quinton; A Ribeiro-de-Oliveira; MR Gadelha; V Popovic; JP Monson; JAH Wass; LA Frohman; AB Grossman; M Korbonits

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Endocrine Abstracts (2007) 14 P605

ECE2007 Poster Presentations (1) (659 abstracts)

Familial acromegaly – the role of the AIP gene

M Gueorguiev ¹ , F Lolli ¹ , JP Chapple ¹ , R Quinton ² , A Ribeiro-de-Oliveira ³ , MR Gadelha ⁴ , V Popovic ⁵ , JP Monson ¹ , JAH Wass ⁶ , LA Frohman ⁷ , AB Grossman ¹ & M Korbonits ¹

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¹Barts and the London Medical School, London, United Kingdom; ²Royal Victoria Infirmary and University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom; ³Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; ⁴Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Brazil; ⁵University Clinical Centre, Belgrade, Serbia; ⁶Churchill Hospital, Oxford, United Kingdom; ⁷University of Illinois, Chicago, United States.

Pituitary adenomas are present in ∼25% of autopsy samples, and recent studies have also suggested that clinically important pituitary adenomas are some 5 times more common than previously recognised. Acromegaly is almost always due to a sporadic growth-hormone secreting pituitary adenoma, but familial acromegaly has been reported occasionally. Linkage and loss of heterozygosity studies have shown that it is caused by a tumour suppressor gene located at 11q13; very recently 3 families have been reported with a very low penetrance mutation in the gene coding for the aryl hydrocarbon receptor (AhR) interactive protein (AIP), a molecular chaperone, which has been linked to the induction of hepatic detoxifying gene products in response to environmental toxins such as dioxin. However, an additional function appears to be regulation of the cell cycle, suppressing cyclin E and increasing expression of p27, which we have previously shown to be involved in pituitary tumorigenesis.

We studied 19 families with familial pituitary adenoma and identified mutations in the AIP gene in a 4/19, which were either stop codons or mutations disrupting the protein-binding segments of the protein. The penetrance of the disease at the time of the study was 64%, suggesting a much higher level of penetrance than previously reported; in some families there was 100% penetrance. A selected group of young-onset sporadic acromegalic patients, including 3 with gigantism, showed no germline mutations. We found AIP protein expression in normal pituitary and in sporadic pituitary adenomas, while mRNA expression of AIP and its putative partner AhR showed up-regulation, suggesting a compensatory mechanism. Somatic mutations of somatotroph tumours were not seen.

In summary, AIP mutation has been identified in one in four of familial acromegaly kindreds and shows a relatively high penetrance; while mutations of this gene are not involved in the pathogenesis of sporadic somatotroph adenomas, more subtle defects are currently under investigation.