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.

Impact of phosphodiesterase 8B gene rs4704397 variation on thyroid homeostasis in childhood obesity

“…PDE8B encodes a cyclic AMP PDE enzyme (11,25), strongly expressed in the thyroid gland (26,27,28) but undetectable in the pituitary gland, and its influence on thyroid hormone parameters should be via hydrolysis and inactivation of cAMP in the thyroid, in response to (11). Among the several mechanisms suggested to explain increased TSH levels in obesity, the most favoured one is increased leptin-mediated production of pro-TRH (3,28,29,30).…”

“…Each copy of the minor A allele was found to be associated with an increase in TSH concentration of 0.13 mIU/l. Remarkably, this polymorphism is located in intron 1 of PDE8B, a gene that encodes a highaffinity cAMP-specific PDE expressed in the thyroid gland and, likely, regulating TSH signalling (10,11).…”

Mammalian Cyclic Nucleotide Phosphodiesterases: Molecular Mechanisms and Physiological Functions

“…PDE8A occurs in high levels in Leydig cells, where it plays an important role in luteinizing hormone (LH) control of testosterone synthesis (391). PDE8B is abundant in mouse adrenal fasciculata cells, where it modulates steroidogenesisis in response to adrenocroticotropic hormone (ACTH) (382a), and it is also implicated in regulation of thyroid-stimulating hormone (TSH) levels, in adrenocortical disease (149), and in the insulin response of pancreatic islets to glucose (98). PDE10 is abundant in certain neuronal cells and is the target of medications being developed for treatment of several neuropsychiatric disorders (243, 244, 303, 332, 346 -348, 378).…”

Ecological Genetics of Thyroid Hormone Physiology in Humans and Wild Animals

“…Genome-wide association studies have also identified several genes involved in thyroid hormone signaling. Three SNPs at intron 1 of the phosphodiesterase 8B (PDE8B) gene are significantly associated with serum TSH levels [40,41]. PDE8B encodes a high-affinity cAMP-specific phosphodiesterase catalyzing the hydrolysis and inactivation of cAMP.…”