Objective: To identify novel unstable tandem nucleotide repeat loci in uncharacterized ataxia patients.

Background: Microsatellites like tandem nucleotide repeats are of importance to human genome and the variation in their lengths drastically alters phenotypes and causes multiple neurodegenerative disorders including spinocerebellar ataxias, HD, myotonic dystrophy etc. Spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative disorders with different subtypes and characterized by loss of balance, motor coordination, eye movement etc. Although, several mutation mechanisms are known to cause SCAs, but repeat expansion events explains 30-40% cases of hereditary ataxias. Nonetheless, more than 60% of clinically confirmed but genetically uncharacterized ataxia cases concerns clinicians and researchers. These cases further indicate the possibility to interrogate potential genes which contain tandem nucleotide repeats.

Methods: The genome wide identification of genes with tandem repeat loci (i.e. CNG, GAA and CCTG) with at least 4 continuous repeat units by in-silico approach was done. Repeat loci were further segregated based on their sizes in reference genome. Thus selected 40 loci were genotyped for repeat length and its variability in DNA samples of healthy controls by fluorescent labeled primers.

Results: In this study, we have identified 13281 tandem repeat loci (CAG = 2948, CTG = 3095, CGG = 2601, GAA = 4515 and CCTG = 122 loci) with at least 4 continuous repeat units in human genome using in-silico approach. Out of these identified loci, we have selected 79 loci (on the bases of repeat size) as a primary concern and screening of 40 loci was done. Interestingly, 18 tandem repeat loci have shown greater variability in TNR length in control samples. Further, these 18 loci which had shown instability were selected to undergo screening in larger set of patient samples (ataxia phenotype) to detect any TNR expansion event of pathogenic threshold. We have not observed any pathological event in any patient (n=95).

Conclusions: Our results suggest that few of these 18 identified repeat loci may be the potential candidates for causing SCAs. Since the prevalence of all SCAs is not uniformly distributed across the world, investigation of the identified unstable repeat loci in other geographical regions may allow identifying novel TNR loci.

References: 1. Albanese V, Holbert S, Saada C, Meier-Ewert S, Lebre AS, Moriniere S, et al; CAG/CTG and CGG/GCC repeats in human brain reference cDNAs: outcome in searching for new dynamic mutations; Genomics. 1998 Feb 1;47(3):414-8. 2. Matilla-Dueñas A, Corral-Juan M, Volpini V, Sanchez I. The spinocerebellar ataxias: clinical aspects and molecular genetics. Adv Exp Med Biol. 2012;724:351-74.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-strategic-approach-to-understand-microsatellite-repeat-loci-among-indian-spinocerebellar-ataxia-patients/