title: Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis.
abstract: 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.
authors.affiliation: INSERM U781, Département de Génétique, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker Enfants Malades, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Michot
authors.forename: Carine
authors.initials: C
authors.lastname: Le Goff
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Avinash
authors.initials: A
authors.lastname: Abhyankar
authors.forename: Céline
authors.initials: C
authors.lastname: Klein
authors.forename: Esther
authors.initials: E
authors.lastname: Kinning
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Guerrot
authors.forename: Philippe
authors.initials: P
authors.lastname: Flahaut
authors.forename: Alice
authors.initials: A
authors.lastname: Duncombe
authors.forename: Genevieve
authors.initials: G
authors.lastname: Baujat
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Caroline
authors.initials: C
authors.lastname: Thalassinos
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; 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 / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010281:Parathyroid Hormone / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D013972:Thyrotropin / Q000378:metabolism; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D010281:Parathyroid Hormone; D013972:Thyrotropin; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human