title: A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.
abstract: 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.
authors.affiliation: 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.
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Eric
authors.initials: E
authors.lastname: Jullian
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Fernande
authors.initials: F
authors.lastname: Rene-Corail
authors.forename: Herve
authors.initials: H
authors.lastname: Lefebvre
authors.forename: Fritz-Line
authors.initials: FL
authors.lastname: Cephise-Velayoudom
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.forename: Philippe
authors.initials: P
authors.lastname: Chanson
authors.forename: Bernard
authors.initials: B
authors.lastname: Conte-Devolx
authors.forename: Miguel
authors.initials: M
authors.lastname: Lucas
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gentil
authors.forename: Carl D
authors.initials: CD
authors.lastname: Malchoff
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
mesh_terms: 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
chemical_list: 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