Cerebellar ataxia and functional genomics: Identifying the routes to cerebellar neurodegeneration

Abstract

Cerebellar ataxias are progressive neurodegenerative disorders characterized by atrophy of the cerebellum leading to motor dysfunction, balance problems, and limb and gait ataxia. These include among others, the dominantly inherited spinocerebellar ataxias, recessive cerebellar ataxias such as Friedreich's ataxia, and X-linked cerebellar ataxias. Since all cerebellar ataxias display considerable overlap in their disease phenotypes, common pathological pathways must underlie the selective cerebellar neurodegeneration. Therefore, it is important to identify the molecular mechanisms and routes to neurodegeneration that cause cerebellar ataxia. In this review, we discuss the use of functional genomic approaches including whole-exome sequencing, genome-wide gene expression profiling, miRNA profiling, epigenetic profiling, and genetic modifier screens to reveal the underlying pathogenesis of various cerebellar ataxias. These approaches have resulted in the identification of many disease genes, modifier genes, and biomarkers correlating with specific stages of the disease. This article is part of a Special Issue entitled: From Genome to Function.

A homozygous mutation ofVWA3Bcauses cerebellar ataxia with intellectual disability

“…Cultured cells expressing mutant VWA3B were more prone to apoptosis, indicating that VWA3B is involved in the apoptotic signalling pathway in neuronal cells. Using the recent advancement of next generation sequencing and in silico analysis, genetic factors in familial cerebellar ataxia have been demonstrated 10. The pathomechanisms of cerebellar neurodegeneration might be explained by mapping interactome networks.…”

“…The predicted pathway based on the gene function includes protein folding and transport, amino acid metabolism, cell cycle and proliferation, synaptic transmission, apoptosis, etc. The three genes, NINJ1 , BIRC3 and WDFC2 , are presumed to have a biological function of apoptosis in the interactome of cerebellar neurodegeneration 10. Identification of the apoptosis triggered by the mutant VWA3B would further contribute to the elucidation of the pathomechanism.…”

A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay

“…In addition to the dominant trinucleotide repeat disorders that lead to toxic accumulation of unfolded protein [2], the recessive forms of disease are associated with inactivating mutations and usually with early-onset presentations. The genes implicated to date suggest defects in neuronal survival pathways (reviewed in [3]), but many mechanisms are still lacking and most patients elude genetic diagnosis.…”

Reliability of phenotypic early‐onset ataxia assessment: a pilot study

“…24,25 Interestingly, half (6/ 12; 50%) of the 'mixed' ataxic children with a known underlying genetic disorder revealed either GOSR2 or ataxia with vitamin E deficiency gene mutations, which are recognized among ataxic movement disorders. The mixed phenotypic appearance may be understood by the longitudinal GOSR2 disease course, involving progressive myoclonic features by the age of 6 years and older.…”