ECE2013 Oral Communications Bone & Calcium (6 abstracts)
Genetic analysis of CDKN1B gene in familial primary hyperparathyroidism
Elena Pardi 1 , Simona Borsari 1 , Federica Saponaro 1 , Chiara Banti 1 , Natalia Pellegata 3 , Misu Lee 3 , Edda Vignali 1 , Antonella Meola 1 , Marco Mastinu 2 , Stefano Mariotti 2 , Claudio Marcocci 1 & Filomena Cetani 1
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; 3Institute of Pathology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
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).
MEN 1 is an autosomal dominant disorder characterized by tumours in multiple endocrine glands, most commonly parathyroid, enteropancreatic and anterior pituitary glands. To date, germline mutations in the MEN1 gene have been identified in 70–80% of MEN1 kindreds. FIHP has a heterogeneous molecular ethiology, since germline mutations in MEN1, HRPT2 and CASR genes have been reported. Recently, germline mutations of cyclin dependent kinase inhibitor 1B (CDKN1B) gene, encoding the p27 protein, have been identified in 8 kindreds with MEN1 syndrome which were negative to the MEN1 genetic screening.
The aim of this study was to perform a genetic screening of CDKN1B gene in patients with MEN1 syndrome and FIHP (33 and 17, respectively). All MEN1 and FIHP probands were negative for MEN1 gene 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 was performed by a 16-capillaries automatic sequencer.
A novel frameshift germline mutation in CDKN1B gene, c.372_373delCT/p.Asn124AsnfsX2, was identified in a MEN1 proband. A construct expressing p27_c.372_373delCT was generated to assess the functional properties of the mutant protein in vitro. Indirect immunofluorescence demonstrated that the mutant protein is mainly retained in the cytoplasm, affecting the cell cycle inhibitory function of p27 in the nucleus. Our results confirm that germline CDKN1B mutations are involved, althought rarely, in parathyroid tumorigenesis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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