A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.
BACKGROUND
Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome, can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas, and endocrine tumors or be isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC and iPPNAD, but with no apparent genotype-phenotype correlation.


OBJECTIVE
The objectives of the study were a detailed phenotyping for CNC manifestations in 12 kindreds bearing the same PRKAR1A mutation and a study of the consequences of the mutation and a potential founder effect.


METHODS
The study consisted of descriptive case reports.


METHODS
The study was conducted at two referral centers.


METHODS
The patients described in this study were referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently iPPNAD.


RESULTS
We describe a 6-bp polypyrimidine tract deletion [exon 7 IVS del (-7-->-2)] in 12 unrelated kindreds that were referred for Cushing syndrome due to PPNAD. Nine of the patients had no family history; in two, there was a family history of iPPNAD. Only one patient met the criteria for CNC. Relatives carrying the same mutation had no manifestations of CNC or PPNAD, suggesting a low penetrance of this PRKAR1A defect. A founder effect was excluded by extensive genotyping of chromosome 17 markers.


CONCLUSIONS
In conclusion, a small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly iPPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.
Groussin
Lionel
L
Institut National de la Santé et de la Recherche Médicale U 567, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université René-Descartes, Paris 5, 75014 Paris, France.
Horvath
Anelia
A
Jullian
Eric
E
Boikos
Sosipatros
S
Rene-Corail
Fernande
F
Lefebvre
Herve
H
Cephise-Velayoudom
Fritz-Line
FL
Vantyghem
Marie-Christine
MC
Chanson
Philippe
P
Conte-Devolx
Bernard
B
Lucas
Miguel
M
Gentil
Alfonso
A
Malchoff
Carl D
CD
Tissier
Frédérique
F
Carney
J Aidan
JA
Bertagna
Xavier
X
Stratakis
Constantine A
CA
Bertherat
Jérôme
J
D000293:Adolescent; D000303:Adrenal Cortex Diseases / Q000235:genetics*; D000328:Adult; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D004247:DNA; D003513:Cycloheximide; D017868:Cyclic AMP-Dependent Protein Kinases