ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 11 OC45

Genotype/phenotype correlation of PRKAR1A mutations in patients with Carney complex (CNC) and/or sporadic primary pigmented nodular adrenocortical disease (PPNAD) from the CNC network

L Groussin1, F Rene-Corail1, L Cazabat1, E Jullian2, E Clauser2, X Bertagna1 & J Bertherat3

1Institut Cochin, INSERM U567, Endocrinology, Paris, France; 2Unité d’Oncogénétique, CHU Cochin, Paris, France; 3Carney Complex Network, GIS-INSERM, Paris, France.

CNC is an autosomal dominant multiple neoplasia syndrome, responsible mainly for cardiac myxomas, pigmented skin lesions and endocrine tumors (acromegaly, thyroid and testicular neoplasms and primary pigmented nodular adrenocortical disease: PPNAD). The PRKAR1A gene was previously found to be mutated in about 41% of CNC kindreds. Most mutations lead to nonsens mediated mRNA decay and preclude expression of the mutant protein. 102 patients (64 with PPNAD and 38 with CNC) from 72 different kindred have been studied. A total of 68 patients were found to have a PRKAR1A inactivating heterozygous mutation (27 different mutations). Among the 72 index cases a PRKAR1A mutation was found in 9/11 (82%) in the group of sporadic CNC cases with PPNAD and 12/14 (86%) in the group of patients with familial CNC. In the group of patient meeting the diagnostic criteria for CNC but without PPNAD nor familial history the mutation rate was lower: 4/14 (29%). PRKAR1A mutation was found in 18/33 (55%) of patients presenting with isolated and sporadic PPNAD. One mutation (Exon 7 IVS del –7-2) was found in 12 different index cases and associated with isolated PPNAD, suggesting the first clear example of genotype/phenotype correlation for PRKAR1A mutation. Out of the 68 patients with PRKAR1A mutation, 32 had a splice site mutation, 28 a frameshift or non-sens mutation and 8 patients presented a mutation that should give an abnormal protein. Mutations that should give rise to an abnormal protein or a stop codon were more often associated with lentiginosis, cardiac myxomas and thyroid nodes by comparison with splice site mutations.

This database demonstrates the very high rate of PRKAR1A mutation in patient with familial CNC or sporadic CNC with PPNAD, shows a genotype/phenotype correlation for some mutations and suggest genetic heterogeneity currently under study for patients with isolated PPNAD.

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