T45. genetic structure of ppp2r2b locus in sca12 patients from india

The spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders that are often inherited and share a complex neurological presentation of ataxia, and often a progressive course. 41 genetic loci have been assigned to particular SCAs. In one of these, SCA12, the disease is the result of an expanded (CAG)n, in the 5′ of the PPP2R2B gene. The SCA12 (CAG)n expansion is a common ataxia encountered in the clinics in northern and eastern India and seems to be disproportionately detected in a particular lineage. There is varying severity, and also comorbid psychiatric symptoms, with neurological syndromes. This may, in part, be linked to tissue-specific trinucleotide repeat instability in the brain. We estimated CAG sizes for 208 individuals referred from the Genetic Counselling and Testing (GCAT) clinic at NIMHANS, Bangalore. To explore the underlying genetic structure of the sequences around the gene, and the CAG stretch, we also genotyped the patient samples using the Global Screening array V3 and constructed LD maps of this region. This included both those who had tested positive for SCA12 patients and those who had not. We also utilized sequence data from the 1000 genomes project to construct similar maps for other world populations. Post-mortem brain CAG sizing at the PPP2R2B locus was done for a SCA12 brain sourced from the NIMHANS brain bank, for five brain regions: cerebellum, temporal, entorhinal cortex, frontal and superior temporal gyrus, as compared to age-matched control brains. We identified 29 patients with an expanded allele (>43 CAG repeats) at our hospital. These patients had one normal CAG repeat allele, ranging from 9-38 (9 being most common); and a larger pathogenic allele with CAG repeats ranging from 44-65. Individuals who did not have an expanded allele for SCA12 had CAG repeats in the range of 1-32, with 9 repeats again being the most frequent and 9.94 being the average. Overall, more than half (51.5%) had either 9 or 12 CAG repeats in at least one of the chromosomes. The LD structure for the 466kb region seemed to be broadly conserved across populations. Interestingly, but expectedly, this LD structure seemed to be slightly disrupted in individuals who were SCA12 positive. This suggests a recent deviation from the base population over the past millennium. Estimates of CAG size of the SCA12 post-mortem brain samples showed varying levels of somatic mosaicism. The instability index ranged from -3.9 (cerebellum) to 11.5 (entorhinal cortex). Understanding both population genetics, as well as tissue genetics may be critical to understanding the pathobiology of SCA12. It is important to understand the molecular genetics of this locus which is the causative gene for SCA12; one of the most prevalent causes of ataxia in many parts of India.