VPS53 mutations cause progressive cerebello-cerebral atrophy type 2

Posted by & filed under Part 28: NEUROGENETICS, _.

Feinstein M et al. VPS53 mutations cause progressive cerebello-cerebral atrophy type 2. J Med Genet. 2014 Feb 27. doi: 10.1136/jmedgenet-2013-101823. [Epub ahead of print]

Progressive cerebello-cerebral atrophy (PCCA), first described in 2003 in six Sephardi Jewish families, is a devastating autosomal recessive neurodegenerative condition presenting in childhood with psychomotor regression, acquired microcephaly, spastic quadriplegia and epilepsy. Neuroimaging studies show a gradual onset of cerebellar, then cerebral white and grey matter atrophy (1). In some families, the causal gene was found to be SEPSECS, which encodes a key enzyme in the synthesis of selenocysteine;  SEPSECS mutations did not account for all cases, suggesting genetic heterogeneity.

In this study, Feinstein et al identify a VPS53 as the causal gene in these families through a combination of genome-wide linkage analysis and whole-exome sequencing; all 10 affected patients studied were compound heterozygous for two recurring mutations. They then proceed to:

– estimate the carrier rate for the recurring VPS53 mutations in the Moroccan Jewish population as approximately 1/37, which could potentially justify carrier screening in this population (although more studies would probably be needed to estimate the prevalence of founder mutations in VPS53 in the Sephardic Jewish population as a whole).

– conduct functional studies that point to a novel disease mechanism, distinct from that underlying SEPSECS-related PCCA. VPS53 encodes one of the four subunits of the Golgi-associated retrograde protein (GARP), which is located in the trans-Golgi and is involved in retrograde vesicular transport, including the recycling of lysosomal sorting receptors. The precise pathogenetic mechanism, however, remains undetermined.


(1) Ben-Zeev B. Progressive cerebellocerebral atrophy: a new syndrome with microcephaly, mental retardation, and spastic quadriplegia. J Med Genet. 2003 Aug;40(8):e96.

Posted by Alina Levtova, MD


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