Exome Sequencing Identifies PDE4D Mutations in Acrodysostosis

• Published in: American journal of human genetics Vol. 90; no. 4; pp. 746 - 751
• Main Authors: Lee, Hane, Graham, John M., Rimoin, David L., Lachman, Ralph S., Krejci, Pavel, Tompson, Stuart W., Nelson, Stanley F., Krakow, Deborah, Cohn, Daniel H.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 06-04-2012; Cell Press; Elsevier
• Subjects: Base Sequence; Biological and medical sciences; Congenital diseases; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit - genetics; Cyclic Nucleotide Phosphodiesterases, Type 3 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 4; Dysostoses - diagnostic imaging; Dysostoses - genetics; Enzymes; Exome - genetics; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Heterozygote; Hormones; Humans; Intellectual Disability - diagnostic imaging; Intellectual Disability - genetics; Male; Medical genetics; Medical sciences; Missense mutation; Molecular and cellular biology; Molecular Sequence Data; Mutation; Osteochondrodysplasias - diagnostic imaging; Osteochondrodysplasias - genetics; phosphodiesterase; Protein kinase A; Radiography; Regulatory subunits; Sequence Analysis, DNA; Human; Genetics; Mutation; Nucleotide sequence; Sequencing
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2012.03.004

Acrodysostosis is a dominantly-inherited, multisystem disorder characterized by skeletal, endocrine, and neurological abnormalities. To identify the molecular basis of acrodysostosis, we performed exome sequencing on five genetically independent cases. Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the cases. Two of the mutations were demonstrated to have occurred de novo, providing strong genetic evidence of causation. Two additional cases were heterozygous for de novo missense mutations in PRKAR1A, which encodes the cAMP-dependent regulatory subunit of protein kinase A and which has been recently reported to be the cause of a form of acrodysostosis resistant to multiple hormones. These findings demonstrate that acrodysostosis is genetically heterogeneous and underscore the exquisite sensitivity of many tissues to alterations in cAMP homeostasis.