Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.

Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis.
AuthorsCaroline Michot, Carine Le Goff, Alice Goldenberg, Avinash Abhyankar, Céline Klein, Esther Kinning, Anne-Marie Guerrot, Philippe Flahaut, Alice Duncombe, Genevieve Baujat, Stanislas Lyonnet, Caroline Thalassinos, Patrick Nitschke, Jean-Laurent Casanova, Martine Le Merrer, Arnold Munnich, Valérie Cormier-Daire
JournalAmerican journal of human genetics (Am J Hum Genet) Vol. 90 Issue 4 Pg. 740-5 (Apr 6 2012) ISSN: 1537-6605 [Electronic] United States
PMID22464250 (Publication Type: Journal Article)
CopyrightCopyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
  • PRKAR1A protein, human
  • Parathyroid Hormone
  • Thyrotropin
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human
  • Adolescent
  • Adult
  • Base Sequence
  • Child
  • Child, Preschool
  • Cyclic AMP-Dependent Protein Kinase RIalpha Subunit (genetics)
  • Cyclic Nucleotide Phosphodiesterases, Type 3 (genetics)
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Dysostoses (genetics)
  • Exome (genetics)
  • Female
  • Humans
  • Intellectual Disability (genetics)
  • Male
  • Molecular Sequence Data
  • Mutation
  • Osteochondrodysplasias (genetics)
  • Parathyroid Hormone (metabolism)
  • Sequence Analysis, DNA
  • Signal Transduction (genetics)
  • Thyrotropin (metabolism)
  • Young Adult

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