SCA5 is caused by dominant mutations in the gene for ‘beta-III spectrin’, a membrane scaffold protein known to play an important role in the cerebellum. Publishing in PLOS Genetics, the team have identified a more serious recessive ataxia related to SCA5 which is caused by a homozygous stop codon mutation in the beta-III spectrin gene. The homozygous condition causes a novel disorder named ‘SPARCA1’ (Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1), which is associated with a severe childhood ataxia and marked cognitive impairment.
This is the first report of any spectrin-related disorder where both copies of the gene are faulty and has given important insights into both SCA5 and SPARCA1.
Whole genome sequencing and genome-wide mapping, performed at the Wellcome Trust Centre for Human Genetics in Oxford, in addition to the characterization of brain abnormalities in beta-III spectrin knockout mice by team members from Edinburgh (led by Dr Mandy Jackson, who obtained her DPhil at the now Weatherall Institute for Molecular Medicine in Oxford) links the beta-III spectrin defect to changes in nerve-cell shape in brain areas associated with cognition and coordination of movements. The work shows that loss of normal beta-III spectrin function underlies both SPARCA1 and SCA5, but a greater loss of beta-III spectrin is required before cognition problems arise.
This study provides novel evidence for a broad role of spectrin in normal brain function beyond the cerebellum, in both cortical brain development and cognition. There are many brain spectrins and the team are now searching for other abnormalities of spectrin function, as they believe these are part of an expanding group of conditions known as “neuronal spectrinopathies”.
For the full paper please visit the PLOS Genetics website.