VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2)
- Miora Feinstein1,
- Hagit Flusser2,
- Tally Lerman-Sagie3,
- Bruria Ben-Zeev4,
- Dorit Lev3,
- Orly Agamy1,
- Idan Cohen1,
- Rotem Kadir1,
- Sara Sivan1,
- Esther Leshinsky-Silver3,
- Barak Markus1,
- Ohad S Birk1,5
- 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
- 2Zussman Child Development Center, Soroka Medical Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- 3Pediatric Neurology Unit, Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel
- 4Pediatric Neurology Unit, Sheba Medical Center, Ramat-Gan, Israel
- 5Genetics Institute, Soroka Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel
- Correspondence to Dr Ohad S Birk, Genetics Institute, Soroka Medical Center, Beer-Sheva 84101, Israel;
- 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.