RESUMEN
The R-loop is a three-stranded nucleic acid structure, which consists of a RNA: DNA hybrid and a DNA single strand. R-loop can be divided into two types: physiological and pathological. The physiological R-loop is involved in many physiological processes such as DNA replication, transcription, and gene expression regulation, while the pathological R-loop induces DNA damage and genome rearrangement. There are many factors that affect the formation of R-loops. Unregulated R-loops destroy genomic stability by interfering with DNA replication and double-strand DNA break repair, and can cause cancer. Therefore, the regulation of R-loops is very important. RNA/ DNA helicase Senataxin (SETX), DEAD-box helicase 5 (DDX5), ribonuclease H (RNase H) and DNA topoisomerase I (topo) play an important role in regulating the balance of R-loops in vivo. Among them, SETX is one of the most characteristic R-loop decomposing enzymes, which can dissolve the R-loops produced during transcriptional termination sites, replication-transcriptional conflicts and DNA damage repair. Senataxin mutations will lead to ataxia with eye movement apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4). Currently there are still many unsolved issues, although many in-depth studies of R-loops have been carried out. Therefore, the structure and function of physiological and pathological R-loops still need to be further explored. This review mainly focuses on the definition and classification of R-loops, the factors that affect the formation of R-loops, the influence of R-loops on genomic stability and R-loop-related diseases, and explores the possibility of using R-loops as a therapeutic target in the future.
RESUMEN
BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.