Expanding genes, repeating themes and therapeutic schemes: The neurobiology of tandem repeat disorders

It is two decades since a first draft sequence of the human reference genome (from a small number of individuals) was published. Whilst this was understandably acclaimed by many as an end in itself, we now realise that this was only the beginning. One ongoing goal could be to eventually obtain whole genome sequences for the majority of the approximately 8 billion extant humans, to improve their health and facilitate the prevention and treatment of a wide range of disorders. However, in order to achieve such lofty global ambitions (which will of course face various hurdles including economic barriers and the many challenges of functional genomics) we must fully understand all of the human genome, including approximately half of it which consists of repetitive sequences, known collectively as the repeatome (Hannan, 2018). Within this repeatome, there are over a million tandemly repeated sequences, or tandem repeats, distributed throughout both coding and non-coding regions of the genome. These tandem repeats exist not only in the human genome, but in the genomes of almost every other species, and have been found to have diverse roles in the expression, structure and function of nucleic acids and proteins, leading to a diverse range of important modulatory impacts on organismal health and disease (Hannan, 2018). Whilst our understanding of the vast majority of these tandem repeats remains in its infancy, the past three decades of research have enhanced our understanding of tandem repeat disorders, mainly in a monogenic Mendelian context, with tandem repeat expansions in specific genes leading to over 50 different human disorders (Khristich and Mirkin, 2020; Sato et al., 2020). Collectively, this is a very substantial burden of disease and the majority of these tandem repeat disorders involve neurological symptoms, often accompanied by psychiatric symptoms, thus providing mechanistic insights into various common CNS disorders. These tandem repeat disorders are as diverse as the tandem repeat sequences, and associated ‘genetic stutters’, that underlie their various gene mutations. These disorders can be recessive or dominant, autosomal or X-linked, and the tandem repeats can be coding or non-coding. The pathogenic mechanisms involve a wide range of molecular mechanisms, including changes to epigenetic regulation, RNA structure and function, and protein structure and function (Hannan, 2018). In the first article in this Special Issue, Rodriguez and Todd (2019) provide an excellent review of these tandem repeat disorders. These disorders impact a diverse variety of molecular and cellular processes, as well as a variety of different cell types, neural circuits and biological systems. Some tandem repeat disorders primarily affect development, whereas many others are degenerative, and each exhibit distinct spatiotemporal patterns of pathogenesis and associated symptomatology. The rate of discovery in the past three decades, since the first tandem repeat mutations were reported to cause such disorders in 1991, is breathtaking, although it is possible that we are still at ‘the tip of the iceberg’ in this dynamic field. The pathogenesis of fragile X syndrome and related disorders is expertly reviewed by Salcedo-Arellano et al. (2020). Fragile X syndrome was one of the first tandem repeat disorders to be described. The trinucleotide (CGG) repeat is located in the 5′ untranslated region (UTR) of the FMR1 gene, which encodes FMRP, a protein implicated in various aspects of neuronal development and plasticity. The latest understanding of pathogenesis of fragile X syndrome (a neurodevelopmental disorder that can include autism and other syndromic symptoms), from molecular and cellular mechanisms to developmental abnormalities and associated functional impairments, is integrated with current clinical knowledge (Salcedo-Arellano et al., 2020). However, rather than causing fragile X syndrome alone, this tandem repeat in FMR1 has been associated with other ‘fragile X disorders', including fragile X tremor-ataxia syndrome (FXTAS). Whilst fragile X syndrome results from large CGG repeat expansions in FMR1, which lead to epigenetic silencing and reduced FMRP, FXTAS involves intermediatelength CGG repeats which appear to be associated both with RNA toxicity and protein toxicity. The protein toxicity has been found to be associated with repeat-associated non-ATG (RAN) translation, which has been discovered in the past decade to be a major contributor to a range of different tandem repeat disorders (Nguyen et al., 2019). Whilst great progress has been made in understanding fragile X disorders, the challenge of producing effective therapies remains an urgent priority in this coming decade. In the next article of this Special Issue, Lanni and Pearson (2019) discuss key findings informing congenital myotonic dystrophy, which was one of the first conditions to be identified as a tandem repeat disorder. Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion the 3’UTR of the DMPK gene. This congenital form of myotonic dystrophy is a neuromuscular disorder caused by large CTG trinucleotide repeat expansions. The molecular impacts of this tandem repeat expansion, including epigenetic modifications, is reviewed in detail, and interpreted in the context of the inheritance and pathogenesis of DM1. This progress in our understanding of the pathogenesis of DM1 provides tantalising glimpses of potential ‘precision medicine’ approaches to this tandem repeat disorder. Within the last decade, it has been discovered that a hexanucleotide repeat expansion in the C9ORF72 gene is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and is a major cause of frontotemporal dementia. One striking aspect of this discovery was that the C9ORF72 hexanucleotide repeat not only contributes to the familial (Mendelian) forms of ALS and FTD, but has also been found