title: PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance.
abstract: BACKGROUND
  Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway.
  
  
  OBJECTIVE
  Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis.
  
  
  METHODS
  Sixteen unrelated patients with acrodysostosis underwent a candidate-gene approach and were investigated for phenotypic features.
  
  
  RESULTS
  All patients had heterozygous de novo mutations. Fourteen patients carried a PRKAR1A mutation (PRKAR1A patients), five each a novel PRKAR1A mutation (p.Q285R, p.G289E, p.A328V, p.R335L, or p.Q372X), nine the reported PRKAR1A p.R368X mutation; two patients harbored a mutation in PDE4D (PDE4D patients) (one novel mutation, p.A227S; one reported, p.E590A). All PRKAR1A, but none of the PDE4D mutated patients were resistant to PTH and TSH. Two PRKAR1A patients each with a novel mutation presented a specific pattern of brachydactyly. One PDE4D patient presented with acroskyphodysplasia. Additional phenotypic differences included mental retardation in PDE4D patients. In addition, we report the presence of pigmented skin lesions in PRKAR1A and PDE4D patients, a feature not yet described in the acrodysostosis entity.
  
  
  CONCLUSIONS
  All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 986 et Centre de Reference des Maladies Rares du Phosphate et du Calcium, Hôpital de Bicêtre, 94276 Le Kremlin Bicêtre Cedex, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Linglart
authors.forename: Helena
authors.initials: H
authors.lastname: Fryssira
authors.forename: Olaf
authors.initials: O
authors.lastname: Hiort
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.forename: Guiomar
authors.initials: G
authors.lastname: Perez de Nanclares
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Claudine
authors.initials: C
authors.lastname: Heinrichs
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.forename: Philippe
authors.initials: P
authors.lastname: Wicart
authors.forename: Virginie
authors.initials: V
authors.lastname: Chassot
authors.forename: Dorothée
authors.initials: D
authors.lastname: Schmidt
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Rubio-Cabezas
authors.forename: Annette
authors.initials: A
authors.lastname: Richter-Unruh
authors.forename: Sara
authors.initials: S
authors.lastname: Berrade
authors.forename: Arrate
authors.initials: A
authors.lastname: Pereda
authors.forename: Emese
authors.initials: E
authors.lastname: Boros
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Muñoz-Calvo
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Gunes
authors.forename: Guylene
authors.initials: G
authors.lastname: Bertrand
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
authors.forename: Caroline
authors.initials: C
authors.lastname: Silve
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics* / Q000502:physiology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics* / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003940:Diagnostic Techniques, Endocrine; D004351:Drug Resistance / Q000235:genetics*; D004413:Dysostoses / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006728:Hormones / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008607:Intellectual Disability / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010009:Osteochondrodysplasias / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013577:Syndrome; D018382:Thyroid Hormone Resistance Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D006728:Hormones; C517834:PRKAR1A protein, human; D010281:Parathyroid Hormone; D043562:Receptors, G-Protein-Coupled; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human