Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis |
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| Institution: | 1. Department of Medical Genetics, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan;2. Department of Laboratory Medicine and Genetics, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;3. Health Sciences University of Hokkaido, Hokkaido, Japan;4. Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK;5. Department of Genetics, University of Cambridge, Cambridge, UK;6. Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan;7. Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan;8. Department of Pediatric Imaging, Tokyo Metropolitan Children''s Medical Center, Tokyo, Japan;9. Seitoku University, Chiba, Japan;10. Department of Radiology, Gachon University Gil Medical Center, Incheon, Republic of Korea;11. Department of Medical Genetics Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea;12. Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea;13. Department of Pediatrics Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea;14. Clinical Research Center, Samsung Biomedical Research Institute, Seoul, Republic of Korea;15. Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea;p. Division of Integrative Biosciences and Biotechnology and School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang, Republic of Korea;q. Macrogen Inc., Seoul, Republic of Korea;s. Center for Advanced Computation, Korea Institute for Advanced Study, Republic of Korea;t. School of Computational Sciences, Korea Institute for Advanced Study, Republic of Korea;u. Mogam Biotechnology Research Institute, Yongin, Republic of Korea;v. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Republic of Korea;w. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;x. Division of Developmental Disabilities, The Misakaenosono Mutsumi Developmental, Medical and Welfare Center, Isahaya, Japan;y. Department of Orthopaedic Surgery, Mie Prefectural Kusanomi Rehabilitation Center, Tsu, Japan;z. Section of Clinical Genetics, Department of Pediatrics, Tenshi Hospital, Sapporo, Japan;11. Institute of Pharmaceutical Science, King''s College, London, UK |
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| 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. |
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