Exome sequencing identifies PDE4D mutations in acrodysostosis.

TitleExome sequencing identifies PDE4D mutations in acrodysostosis.
Publication TypeJournal Article
Year of Publication2012
AuthorsLee, H, Graham JM, Rimoin DL, Lachman RS, Krejci P, Tompson SW, Nelson SF, Krakow D, Cohn DH
JournalAmerican journal of human genetics
Date Published2012 Apr 6
KeywordsBase Sequence, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Cyclic Nucleotide Phosphodiesterases, Type 3, Dysostoses, Exome, Female, Heterozygote, Humans, intellectual disability, Male, Molecular Sequence Data, Mutation, Osteochondrodysplasias, Sequence Analysis, DNA

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.

Alternate JournalAm. J. Hum. Genet.