J Med Genet 51:303-308 doi:10.1136/jmedgenet-2013-101823
  • New disease loci
  • Short report

VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2)

  1. Ohad S Birk1,5
  1. 1Morris 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
  2. 2Zussman Child Development Center, Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
  3. 3Pediatric Neurology Unit, Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel
  4. 4Pediatric Neurology Unit, Sheba Medical Center, Ramat-Gan, Israel
  5. 5Genetics Institute, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
  1. Correspondence to Dr Ohad S Birk, Genetics Institute, Soroka Medical Center, Beer-Sheva 84101, Israel; obirk{at}
  • Received 23 May 2013
  • Revised 6 January 2014
  • Accepted 3 February 2014
  • Published Online First 27 February 2014


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.