Advances in Sequencing Technologies for Understanding Hereditary Ataxias: A Review

Abstract

Importance: The hereditary progressive ataxias comprise genetic disorders that affect the cerebellum and its connections. Even though these diseases historically have been among the first familial disorders of the nervous system to have been recognized, progress in the field has been challenging because of the large number of ataxic genetic syndromes, many of which overlap in their clinical features.

Observations: We have taken a historical approach to demonstrate how our knowledge of the genetic basis of ataxic disorders has come about by novel techniques in gene sequencing and bioinformatics. Furthermore, we show that the genes implicated in ataxia, although seemingly unrelated, appear to encode for proteins that interact with each other in connected functional modules.

Conclusions and relevance: It has taken approximately 150 years for neurologists to comprehensively unravel the genetic diversity of ataxias. There has been an explosion in our understanding of their molecular basis with the arrival of next-generation sequencing and computer-driven bioinformatics; this in turn has made hereditary ataxias an especially well-developed model group of diseases for gaining insights at a systems level into genes and cellular pathways that result in neurodegeneration.

Figure 1. Next-Generation Sequencing (NGS) Technologies and the Discovery Rate for Ataxia Genes

The graph shows the cumulative number of genes involved in ataxia syndromes that have been identified every year. Milestones in genome research and nucleic acid sequencing are highlighted. Since the introduction of NGS in 2004, the number of genetically characterized ataxias has exponentially grown every year. Before NGS, 27 genes had been identified for autosomal dominant ataxias, 35 genes for recessive ataxias, 4 genes for X-linked ataxias, and 3 genes for mitochondrial ataxias. Since then, NGS has led to the identification of 13 autosomal dominant ataxias, 36 recessive ataxias, and 2 X-linked ataxias.

Figure 2. Protein Interaction Network for Human Ataxia Genes

The STRING prediction server (version 9.1) was used to generate the protein network using all the known genes involved in human ataxia syndromes as seeds. The maximum number of predicted neighbors was set to 1000; experiment was selected as search criteria (to include only the experimentally validated physical interactions), and the maximum stringency was chosen (highest confidence score = 0.900). The following 6 subnetworks can be appreciated, each highlighting a specific cellular process: protein translation (red), ubiquitination (blue), transcription regulation (yellow and green), DNA repair (brown), and energy production (orange). TBP indicates TATA-binding protein. A complete list of protein names and symbols is given in eTable 3 in the Supplement. SCA41 and SCA43 were not included because they were published after the manuscript was accepted.