Large Deletions of the PRKAR1A Gene in Carney Complex

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 41-52-HPA Axis & Disease States
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-47
Paraskevi Salpea*1, Anelia Dafinova Horvath2, Edra London1, Annalisa Vetro3, Alison Manning4, Evgenia Gourgari1, Margaret Keil1, Antonella Forlino3, Orsetta Zuffardi3 and Constantine A Stratakis1
1National Institutes of Health (NIH), Bethesda, MD, 2The George Washington University, Washington, DC, 3University of Pavia, Pavia, Italy, 4Brigham and Women's Hospital, Boston, MA
Carney Complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, and different types of endocrine tumors. PRKAR1A gene encodes for the type 1A regulatory subunit of protein kinase A and inactivating mutations have been shown to cause Carney complex (~70% of CNC patients). Most of these mutations consist of single base substitutions, small deletions, insertions or combined rearrangements, all of them not exceeding 15bp.

In this study we report large PRKAR1A gene deletions in 7 CNC patients. The deletions were identified by microarray-based Comparative Genomic Hybridization (array-CGH) and confirmed by Sanger sequencing of the boundaries and, in one case of complete deletion of the PRKAR1A gene - through Fluorescent in situ Hybridization (FISH). Quantitative PCR showed that these deletions lead to decreased PRKAR1A mRNA levels. Thus, we show that deletions of PRKAR1A cause CNC through haploinsufficiency, which is the molecular mechanism of the disease in the vast majority of the PRKAR1A point mutation carriers.

These deletions spread through all functional R1a domains and with significantly decreased PRKAR1A expression compared to normal. Interestingly preliminary clinical data indicated that these patients with extended PRKAR1A deletions also shared a different phenotype.

Until now only several cases of CNC patients with large PRKAR1A deletions have been described. In this study we present new cases that extend PRKAR1A mutational spectrum. Our data suggest that testing for large PRKAR1A alterations might need to be considered for routine genetic diagnosis of CNC.

Nothing to Disclose: PS, ADH, EL, AV, AM, EG, MK, AF, OZ, CAS

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