title: VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2).
abstract: BACKGROUND
  Progressive cerebello-cerebral atrophy (PCCA) leading to profound mental retardation, progressive microcephaly, spasticity and early onset epilepsy, was diagnosed in four non-consanguineous apparently unrelated families of Jewish Moroccan ancestry. Common founder mutation(s) were assumed.
  
  
  METHODS
  Genome-wide linkage analysis and whole exome sequencing were done, followed by realtime PCR and immunofluorescent microscopy.
  
  
  RESULTS
  Genome-wide linkage analysis mapped the disease-associated gene to 0.5 Mb on chromosome 17p13.3. Whole exome sequencing identified only two mutations within this locus, which were common to the affected individuals: compound heterozygous mutations in VPS53, segregating as expected for autosomal recessive heredity within all four families, and common in Moroccan Jews (∼1:37 carrier rate). The Golgi-associated retrograde protein (GARP) complex is involved in the retrograde pathway recycling endocytic vesicles to Golgi; c.2084A>G and c.1556+5G>A VPS53 founder mutations are predicted to affect the C-terminal domain of VPS53, known to be critical to its role as part of this complex. Immunofluorescent microscopy demonstrated swollen and abnormally numerous CD63 positive vesicular bodies, likely intermediate recycling/late endosomes, in fibroblasts of affected individuals.
  
  
  CONCLUSIONS
  Autosomal recessive PCCA type 2 is caused by VPS53 mutations.
authors.affiliation: Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel.
authors.forename: Miora
authors.initials: M
authors.lastname: Feinstein
authors.forename: Hagit
authors.initials: H
authors.lastname: Flusser
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Orly
authors.initials: O
authors.lastname: Agamy
authors.forename: Idan
authors.initials: I
authors.lastname: Cohen
authors.forename: Rotem
authors.initials: R
authors.lastname: Kadir
authors.forename: Sara
authors.initials: S
authors.lastname: Sivan
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.forename: Barak
authors.initials: B
authors.lastname: Markus
authors.forename: Ohad S
authors.initials: OS
authors.lastname: Birk
mesh_terms: D000293:Adolescent; D000328:Adult; D001284:Atrophy / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology*; D002675:Child, Preschool; D002874:Chromosome Mapping; D005260:Female; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D033921:Vesicular Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C087215:LRRC32 protein, human; D008565:Membrane Proteins; C503307:VPS53 protein, human; D033921:Vesicular Transport Proteins