Genetic analysis of AIP genes in familial primary hyperparathyroidism

Federica Saponaro; Simona Borsari; Elena Pardi; Chiara Banti; Edda Vignali; Antonella Meola; Antonella Picone; Marco Mastinu; Stefano Mariotti; Claudio Marcocci; Filomena Cetani

doi:10.1530/endoabs.32.P121

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Endocrine Abstracts (2013) 32 P121 | DOI: 10.1530/endoabs.32.P121

ECE2013 Poster Presentations Calcium and Vitamin D metabolism (62 abstracts)

Genetic analysis of AIP genes in familial primary hyperparathyroidism

Federica Saponaro ¹ , Simona Borsari ¹ , Elena Pardi ¹ , Chiara Banti ¹ , Edda Vignali ¹ , Antonella Meola ¹ , Antonella Picone ¹ , Marco Mastinu ² , Stefano Mariotti ² , Claudio Marcocci ¹ & Filomena Cetani ¹

Err

Author affiliations

¹Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; ²Endocrinology Unit, Department of Medical Sciences, Policlinico di Monserrato, University of Cagliari, Cagliari, Italy.

Primary hyperparathyroidism (PHPT) is usually a sporadic disorder, but in <10% of cases occurs as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2A (MEN1 and MEN2A), hyperparathyroidism–jaw tumor syndrome (HPT–JT) and familial isolated hyperparathyroidism (FIHP).

MEN1 is an autosomal dominant disorder characterized by tumours in multiple endocrine glands, most commonly parathyroid, enteropancreatic and anterior pituitary glands. To date MEN1 gene germline mutations have been identified in 70–80% of MEN1 kindreds. FIHP has a heterogeneous molecular ethiology, since germline mutations of MEN1, HRPT2 and CASR genes have been reported. Germline mutations of the aryl hydrocabon receptor interacting protein (AIP) gene, responsible for 15–25% of familial isolated pituitary adenoma (FIPA) syndrome, have been recently reported in a MEN1 case.

The aim of this study was to perform a genetic screening of AIP gene in 22 MEN1 and 14 FIHP kindreds. All MEN1 kindreds were negative for MEN1 gene mutations and all FIHP families were negative for MEN1, HRPT2, CASR mutations at genetic testing.

Genomic DNA from index cases was analyzed by PCR amplification of the entire coding region and splice sites and direct sequencing by a 16-capillaries automatic sequencer.

Two germline mutations in exon 1 of AIP gene were detected in two MEN1 probands, namely Arg9Gln (c.26G>A) and Arg16His (c.47G>A). Both mutations have already been reported, Arg9Gln in an acromegalic patient, and Arg16His in several FIPA families and patients with apparent sporadic pituitary adenoma. R9Q variant has been described to cause a significant increase in proliferation in cell cultures, while the pathogenetic nature of R16H is still under investigation since it has been identified in few healthy subjects and in some families seems not to segregate with the disease.

Our results suggest that germline AIP mutations may be involved, although rarely, in parathyroid tumorigenesis.