title: Familial isolated primary pigmented nodular adrenocortical disease associated with a novel low penetrance PRKAR1A gene splice site mutation.
abstract: OBJECTIVE
  Primary pigmented nodular adrenocortical disease (PPNAD) is associated with inactivating germline protein kinase A regulatory subunit type 1-alpha (PRKAR1A) mutations and loss of heterozygosity at the 17q22-24 locus in approximately 50% patients. PRKAR1A mutations are observed in both isolated PPNAD (iPPNAD) and Carney complex (CNC). Most mutations result in a functionally null-allele and exhibit high penetrance. We genotyped members of an extended family for a novel PRKAR1A mutation and undertook detailed phenotyping for CNC in the affected individuals.
  
  
  METHODS
  A 10.5-year-old male was diagnosed with PPNAD; the patient's mother also had iPPNAD. A 13-year-old sibling and 7 other relatives (mean age 58.2, range 29.1-80.2 years) were referred for PRKAR1A mutation analysis.
  
  
  RESULTS
  DNA analysis of the index case and parent revealed a novel germline heterozygous PRKAR1A mutation at the +1 position of the acceptor site of intron 3 [c.349 G>T]. The same heterozygous splice site mutation was present in the sibling with no PPNAD or CNC manifestations and 2 other individuals aged 54.9 and 57.1 years who had subclinical Cushing's syndrome but no features of CNC.
  
  
  CONCLUSIONS
  We conclude that c.349 G>T, a novel splice site germline PRKAR1A defect, has low penetrance resulting in incomplete clinical expression in this kindred.
authors.affiliation: Queen Mary University of London, Barts and London School of Medicine and Dentistry, Centre for Endocrinology, William Harvey Research Institute, London, UK. h.l.storr@qmul.ac.uk
authors.forename: Helen L
authors.initials: HL
authors.lastname: Storr
authors.forename: Louise A
authors.initials: LA
authors.lastname: Metherell
authors.forename: Renuka
authors.initials: R
authors.lastname: Dias
authors.forename: Martin O
authors.initials: MO
authors.lastname: Savage
authors.forename: Ase K
authors.initials: AK
authors.lastname: Rasmussen
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: Katharina M
authors.initials: KM
authors.lastname: Main
mesh_terms: D000293:Adolescent; D000303:Adrenal Cortex Diseases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D056733:Carney Complex / Q000235:genetics*; D002648:Child; D003480:Cushing Syndrome / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005190:Family; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D010641:Phenotype; D022821:RNA Splice Sites; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D022821:RNA Splice Sites