title: Haplotype analysis of the promoter region of phosphodiesterase type 8B (PDE8B) in correlation with inactivating PDE8B mutation and the serum thyroid-stimulating hormone levels.
abstract: BACKGROUND
  Human phosphodiesterase (PDE) type 8B (PDE8B) is located at 5q14.1 and is known as the PDE with the highest affinity to cAMP. We recently described a family with bilateral micronodular adrenocortical disease that was apparently caused by an inactivating PDE8B mutation (H305P). As a result of a genome-wide study, a strong association between six polymorphic variants in the PDE8B promoter and serum levels of the thyroid-stimulating hormone (TSH) has been recently reported. Despite an extended analysis of the regions surrounding 5q14.1, no other potential genetic variants that could be responsible for the associated TSH levels were found.
  
  
  METHODS
  In this study, we genotyped by polymerase chain reaction the described six polymorphic variants in the PDE8B promoter in the family with micronodular adrenocortical disease and inactivating PDE8B mutation and analyzed their correlation with individual TSH values in the family members.
  
  
  RESULTS
  We observed complete segregation between the reported association and individual TSH values in the family we studied. Haplotype analysis showed that the haplotype associated with the high TSH levels is different from the one that segregated with H305P, suggesting that the mutation most probably has arisen on an allele independent of the high TSH-associated allele.
  
  
  CONCLUSIONS
  The proposed mechanism by which PDE8B may influence TSH levels is through control of cAMP signaling. Our analysis revealed separate segregation of an inactivating PDE8B allele from the high-TSH-allele and showed low TSH levels in persons who carry an inactivating PDE8B allele. These data suggest that, indeed, PDE8B may be involved in regulation of TSH levels.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Fabio
authors.initials: F
authors.lastname: Faucz
authors.forename: Gabriela P
authors.initials: GP
authors.lastname: Finkielstain
authors.forename: Maria Eleni
authors.initials: ME
authors.lastname: Nikita
authors.forename: Anya
authors.initials: A
authors.lastname: Rothenbuhler
authors.forename: Madson
authors.initials: M
authors.lastname: Almeida
authors.forename: Veronica
authors.initials: V
authors.lastname: Mericq
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics; D000328:Adult; D002675:Child, Preschool; D000242:Cyclic AMP / Q000502:physiology; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015398:Signal Transduction; D013972:Thyrotropin / Q000097:blood* / Q000235:genetics
chemical_list: D013972:Thyrotropin; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human