title: Exome sequencing identifies PDE4D mutations in acrodysostosis.
abstract: 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.
authors.affiliation: Department of Human Genetics, University of California-Los Angeles, CA 90095, USA.
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.forename: David L
authors.initials: DL
authors.lastname: Rimoin
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.forename: Pavel
authors.initials: P
authors.lastname: Krejci
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Tompson
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D001483:Base Sequence; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004413:Dysostoses / Q000000981:diagnostic imaging / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000000981:diagnostic imaging / Q000235:genetics*; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human