title: Mutations in γ adducin are associated with inherited cerebral palsy.
abstract: OBJECTIVE
  Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein-4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease.
  
  
  METHODS
  We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in Drosophila.
  
  
  RESULTS
  We identified a homozygous c.1100G>A (p.G367D) mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin-capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion.
  
  
  CONCLUSIONS
  Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy.
authors.affiliation: Sanford Children's Health Research Center, Sioux Falls, SD.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
authors.forename: Tyler
authors.initials: T
authors.lastname: Jepperson
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Dutta
authors.forename: Robert D
authors.initials: RD
authors.lastname: Steiner
authors.forename: Ellen
authors.initials: E
authors.lastname: Cottenie
authors.forename: Lynn
authors.initials: L
authors.lastname: Sanford
authors.forename: Mark
authors.initials: M
authors.lastname: Merkens
authors.forename: Barry S
authors.initials: BS
authors.lastname: Russman
authors.forename: Peter A
authors.initials: PA
authors.lastname: Blasco
authors.forename: Guang
authors.initials: G
authors.lastname: Fan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Pollock
authors.forename: Sarah
authors.initials: S
authors.lastname: Green
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: Catherine
authors.initials: C
authors.lastname: Mooney
authors.forename: Doris
authors.initials: D
authors.lastname: Kretzschmar
authors.forename: Coro
authors.initials: C
authors.lastname: Paisán-Ruiz
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000818:Animals; D030801:Animals, Genetically Modified; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D002547:Cerebral Palsy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007597:Jordan; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D000099291:Adducins
chemical_list: D002148:Calmodulin-Binding Proteins; D029721:Drosophila Proteins; D000099291:Adducins; C102021:ADD3 protein, human; C108208:hts protein, Drosophila