title: EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations.
abstract: BACKGROUND
  Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.
  
  
  METHODS
  We selected a cohort of 99 PCH patients (90 families) tested negative for mutations in the TSEN genes, RARS2, VRK1 and CASK. Patients in this cohort were referred with a tentative diagnose PCH type 1, 2, 4, 7 or unclassified PCH. Genetic analysis of the EXOSC3 gene was performed using Sanger sequencing. Clinical data, MR images and autopsy reports of patients positive for EXOSC3 mutations were analyzed.
  
  
  RESULTS
  EXOSC3 mutations were found in twelve families with PCH subtype 1, and were not found in patients with other PCH subtypes. Identified mutations included a large deletion, nonsense and missense mutations. Examination of clinical data reveals a prolonged disease course in patients with a homozygous p.D132A mutation. MRI shows variable pontine hypoplasia in EXOSC3 mediated PCH, where the pons is largely preserved in patients with a homozygous p.D132A mutation, but attenuated in patients with other mutations. Additionally, bilateral cerebellar cysts were found in patients compound heterozygous for a p.D132A mutation and a nonsense allele.
  
  
  CONCLUSIONS
  EXOSC3 mediated PCH shows clear genotype-phenotype correlations. A homozygous p.D132A mutation leads to PCH with possible survival into early puberty, and preservation of the pons. Compound heterozygosity for a p.D132A mutation and a nonsense or p.Y109N allele, a homozygous p.G31A mutation or a p.G135E mutation causes a more rapidly progressive course leading to death in infancy and attenuation of the ventral pons.Our findings imply a clear correlation between genetic mutation and clinical outcome in EXOSC3 mediated PCH, including variable involvement of the pons.
authors: Veerle Rc
authors: VR
authors: Eggens
authors: Peter G
authors: PG
authors: Barth
authors: Jikke-Mien F
authors: JM
authors: Niermeijer
authors: Jonathan N
authors: JN
authors: Berg
authors: Niklas
authors: N
authors: Darin
authors: Abhijit
authors: A
authors: Dixit
authors: Joel
authors: J
authors: Fluss
authors: Nicola
authors: N
authors: Foulds
authors: Darren
authors: D
authors: Fowler
authors: Tibor
authors: T
authors: Hortobágyi
authors: Thomas
authors: T
authors: Jacques
authors: Mary D
authors: MD
authors: King
authors: Periklis
authors: P
authors: Makrythanasis
authors: Adrienn
authors: A
authors: Máté
authors: James A R
authors: JA
authors: Nicoll
authors: Declan
authors: D
authors: O'Rourke
authors: Sue
authors: S
authors: Price
authors: Andrew N
authors: AN
authors: Williams
authors: Louise
authors: L
authors: Wilson
authors: Mohnish
authors: M
authors: Suri
authors: Laszlo
authors: L
authors: Sztriha
authors: Marit B
authors: MB
authors: Dijns-de Wissel
authors: Mia T
authors: MT
authors: van Meegen
authors: Fred
authors: F
authors: van Ruissen
authors: Eleonora
authors: E
authors: Aronica
authors: Dirk
authors: D
authors: Troost
authors: Charles Blm
authors: CB
authors: Majoie
authors: Henk A
authors: HA
authors: Marquering
authors: Bwee Tien
authors: BT
authors: Poll-Thé
authors: Department of Genome Analysis, Academic Medical Centre, Amsterdam, the Netherlands. f.baas@amc.uva.nl.
authors: Frank
authors: F
authors: Baas
mesh_terms: D001921:Brain / Q000473:pathology; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D009154:Mutation; D009849:Olivopontocerebellar Atrophies / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: C571397:EXOSC3 protein, human; D016601:RNA-Binding Proteins; D063326:Exosome Multienzyme Ribonuclease Complex