title: Different mutations in PDE4D associated with developmental disorders with mirror phenotypes.
abstract: BACKGROUND
  Point mutations in PDE4D have been recently linked to acrodysostosis, an autosomal dominant disorder with skeletal dysplasia, severe brachydactyly, midfacial hypoplasia and intellectual disability. The purpose of the present study was to investigate clinical and cellular implications of different types of mutations in the PDE4D gene.
  
  
  METHODS
  We studied five acrodysostosis patients and three patients with gene dose imbalances involving PDE4D clinically and by whole exome sequencing, Sanger sequencing and array comparative hybridisation. To evaluate the functional consequences of the PDE4D changes, we used overexpression of mutated human PDE4D message and morpholino-based suppression of pde4d in zebrafish.
  
  
  RESULTS
  We identified three novel and two previously described PDE4D point mutations in the acrodysostosis patients and two deletions and one duplication involving PDE4D in three patients suffering from an intellectual disability syndrome with low body mass index, long fingers, toes and arms, prominent nose and small chin. When comparing symptoms in patients with missense mutations and gene dose imbalances involving PDE4D, a mirror phenotype was observed. By comparing overexpression of human mutated transcripts with pde4d knockdown in zebrafish embryos, we could successfully assay the pathogenicity of the mutations.
  
  
  CONCLUSIONS
  Our findings indicate that haploinsufficiency of PDE4D results in a novel intellectual disability syndrome, the 5q12.1-haploinsufficiency syndrome, with several opposing features compared with acrodysostosis that is caused by dominant negative mutations. In addition, our results expand the spectrum of PDE4D mutations underlying acrodysostosis and indicate that, in contrast to previous reports, patients with PDE4D mutations may have significant hormone resistance with consequent endocrine abnormalities.
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lindstrand
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.forename: Daniel
authors.initials: D
authors.lastname: Nilsson
authors.forename: Maria
authors.initials: M
authors.lastname: Pettersson
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hofmeister
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Anderlid
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.forename: Peter
authors.initials: P
authors.lastname: Gustavsson
authors.forename: Helena
authors.initials: H
authors.lastname: Valta
authors.forename: Stefan
authors.initials: S
authors.lastname: Geiberger
authors.forename: Alexandra
authors.initials: A
authors.lastname: Topa
authors.forename: Kristina
authors.initials: K
authors.lastname: Lagerstedt-Robinson
authors.forename: Fulya
authors.initials: F
authors.lastname: Taylan
authors.forename: Josephine
authors.initials: J
authors.lastname: Wincent
authors.forename: Tobias
authors.initials: T
authors.lastname: Laurell
authors.forename: Minna
authors.initials: M
authors.lastname: Pekkinen
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
mesh_terms: D000818:Animals; D055028:Comparative Genomic Hybridization; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics*; D004413:Dysostoses / Q000175:diagnosis / Q000235:genetics; D019066:Facies; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D023061:Gene Order; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics; D010641:Phenotype; D017354:Point Mutation; D015027:Zebrafish / Q000235:genetics
chemical_list: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human
keywords: Clinical Genetics; Copy-Number; Developmental; Other Endocrinology; Other Neurology