Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis.

Abstract

Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analyzed (Gly673Asp and Ile678Thr; based on PDE4D4 residue numbering). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity, which was identified by increased cAMP levels. However, the cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with a lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia. We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction of other PDE4 isoforms that can be expected to be targeted to different signaling complexes and exert distinct effects on compartmentalized cAMP signaling.

• Authors: Tadashi Kaname, Chang-Seok Ki, Norio Niikawa, George S Baillie, Jonathan P Day, Ken-Ichi Yamamura, Tohru Ohta, Gen Nishimura, Nobuo Mastuura, Ok-Hwa Kim, Young Bae Sohn, Hyun Woo Kim, Sung Yoon Cho, Ah-Ra Ko, Jin Young Lee, Hyun Wook Kim, Sung Ho Ryu, Hwanseok Rhee, Kap-Seok Yang, Keehyoung Joo, Jooyoung Lee, Chi Hwa Kim, Kwang-Hyun Cho, Dongsan Kim, Kumiko Yanagi, Kenji Naritomi, Ko-Ichiro Yoshiura, Tatsuro Kondoh, Eiji Nii, Hidefumi Tonoki, Miles D Houslay, Dong-Kyu Jin
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 11 Pg. 2446-59 (Nov 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 25064455 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• Cyclic AMP-Dependent Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 4
• PDE4D protein, human
• PDE4D protein, rat

Topics

• Adolescent
• Adult
• Amino Acid Substitution
• Animals
• Child
• Child, Preschool
• Cyclic AMP-Dependent Protein Kinases (chemistry, genetics, metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (chemistry, genetics, metabolism)
• Dysostoses (diagnostic imaging, enzymology, genetics)
• Female
• HEK293 Cells
• Heterozygote
• Humans
• Intellectual Disability (diagnostic imaging, enzymology, genetics)
• Male
• Molecular Docking Simulation
• Mutation, Missense
• Osteochondrodysplasias (diagnostic imaging, enzymology, genetics)
• Radiography
• Rats
• Rats, Mutant Strains
• Second Messenger Systems (genetics)