The spinocerebellar ataxias (SCAs) are a clinically heterogenous group of neurodegenerative disorders that affect movement and posture. There are approximately 100 genetic forms of ataxia however many are yet to have their exact cause identified. In the large Australian SCA30 family (OMIM: 613371), disease onsets in the sixth to seventh decade and consists of mild to moderate dysarthria, appendicular ataxia and gait ataxia. Brain MRI shows atrophy of the superior and dorsal cerebellar vermis and cerebellar hemisphere with no other parts of the brain affected.
We linked the cause of SCA30 to 14q32.13 with high probability (cumulative LOD score > 12), and within that region we identified, a rare 331 kb duplication. Transcriptomic analysis of patient lymphoblast cell lines unexpectedly identified a splice-mediated chimeric transcript between two genes that were affected by the duplication; CLMN and SYNE3. The chimeric transcript was predicted to produce a complete, in-frame copy of SYNE3 fused to a short N-terminal peptide corresponding to exon 1 of CLMN. SYNE3 (a.k.a Nesprin 3) forms part of the linker of nucleoskeleton and cytoskeleton complex and is involved in control of gene expression via mechanotransduction. Overexpression of either SYNE3 or the CLMN::SYNE3 fusion in HeLa cells and E17.5 primary mouse cortical neuron cultures showed both proteins equivalently localised to the nuclear envelope, colocalised with SYNE3 interacting proteins such as vimentin and plectin and caused reduction of nuclear volume. We hypothesise that ectopic expression of SYNE3 in cerebellar Purkinje neurons through hijacking the CLMN promoter causes alteration of nuclear structure and reduced cell viability leading to spinocerebellar ataxia in the SCA30 family.
Though well known in cancers, splice-mediated chimeric RNA arising from structural variants that do not cause obvious gene-fusions have rarely been implicated in Mendelian disorders. We suggest chimeric RNA are a potentially overlooked source of genetic diagnoses.