Spinocerebellar ataxias (SCAs) caused by common mutations

Abstract

The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.

Keywords: Ca2+ homeostasis; Common mutations; Disease mechanisms; Spinocerebellar ataxias.

Fig. 1

Negative regulation of TRPC3 by PKC at the postsynaptic membrane (modified from [118]). For details see text. TRPC3, short transient receptor potential channel 3; DAG, diacylglycerol; PKC, protein kinase c; PKG, protein kinase g

Fig. 2

Twenty-one genes that cause spinocerebellar degeneration when mutated (see text and Table 1)

Fig. 3

Subcellular location of polypeptides encoded by 21 genes involved in spinocerebellar degeneration. Note that one gene product can be present in more than one cell compartment. Only locations assigned with highest confidence (levels 4, 5 of genecards) are given. From: https://www.genecards.org/