title: Large deletions of the PRKAR1A gene in Carney complex.
abstract: OBJECTIVE
  Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found in approximately 70% of the patients. To date, no germ-line PRKAR1A deletion and/or insertion exceeded a few base pairs (up to 15). Although a few families map to chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes in PRKAR1A -- mutation-negative individuals with Carney complex.
  
  
  METHODS
  To screen for gross alterations of the PRKAR1A gene, we applied Southern hybridization analysis on 36 unrelated Carney complex patients who did not have small intragenic mutations or large aberrations in PRKAR1A, including the probands from two kindreds mapping to chromosome 2.
  
  
  RESULTS
  We found large PRKAR1A deletions in the germ-line of two patients with Carney complex, both sporadic cases; no changes were identified in the remaining patients, including the two chromosome-2-mapping families. In the first patient, the deletion is expected to lead to decreased PRKAR1A mRNA levels but no other effects on the protein; the molecular phenotype is predicted to be PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing Carney complex. In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic protein kinase A subunit. In vitro transfection studies of the mutant PRKAR1A showed impaired ability to bind cyclic AMP and activation of the protein kinase A enzyme. The patient bearing this mutation had a more-severe-than-average Carney complex phenotype that included the relatively rare psammomatous melanotic schwannoma.
  
  
  CONCLUSIONS
  Large PRKAR1A deletions may be responsible for Carney complex in patients that do not have PRKAR1A gene defects identifiable by sequencing. Preliminary data indicate that these patients may have a different phenotype especially if their defect results in an expressed, abnormal version of the PRKAR1A protein.
authors.affiliation: Section on Endocrinology and Genetics and Pediatric Endocrinology Training Program, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD 20892, USA.
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Ioannis
authors.initials: I
authors.lastname: Bossis
authors.forename: Christoforos
authors.initials: C
authors.lastname: Giatzakis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Levine
authors.forename: Frank
authors.initials: F
authors.lastname: Weinberg
authors.forename: Elise
authors.initials: E
authors.lastname: Meoli
authors.forename: Audrey
authors.initials: A
authors.lastname: Robinson-White
authors.forename: Jennifer
authors.initials: J
authors.lastname: Siegel
authors.forename: Payal
authors.initials: P
authors.lastname: Soni
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Ludmila
authors.initials: L
authors.lastname: Matyakhina
authors.forename: Somya
authors.initials: S
authors.lastname: Verma
authors.forename: Elaine
authors.initials: E
authors.lastname: Remmers
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D002460:Cell Line; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D009377:Multiple Endocrine Neoplasia / Q000235:genetics*
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human