Determining the CAG Repeat Mosaic in Post-mortem Human HD Brains

Ging, H., Nethisinghe, S., Chatzi, A., Ciosi, M. , Monckton, D. G. and Giunti, P. (2018) Determining the CAG Repeat Mosaic in Post-mortem Human HD Brains. EHDN 2018 Plenary Meeting, Vienna, Austria, 14-16 Sep 2018.

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Background: Huntington’s Disease (HD) is fully penetrant when ≥40 CAG repeats are present in the Huntingtin gene. CAG repeat length is inconsistent both between and within germline and somatic tissues, and this instability is most evident in the brain. Such somatic expansions are suggested to contribute to HD progression and neurodegeneration. It has been determined in a small number of Vonsattel grade 0 HD cases that neuronal CAG repeat expansions are more prominent in the striatum than in the cortex. As the disease progresses, this association is reversed. However, the very large expansions previously reported have not been replicated. Aims: To determine the exact CAG repeat sequence and length in six post-mortem human HD brains and corresponding blood, and examine the tissue-specific pattern of somatic mosaicism. Methods: DNA was extracted from brain and blood, sized by fragment analysis, cloned and sequenced by Sanger sequencing, Illumina MiSeq, and PacBio SMRT sequencing. Small-pool PCR was used for repeat length quantification. Results: Large expansions up to 620 CAG repeats are present in end-stage HD human post-mortem brains. The association between the striatum and cortex in relation to the degree of mosaicism is dependent on patient phenotype. With the exception of one sample, the cerebellum and blood are consistently stable. Conclusions: Repeat expansions up to 15x the diagnostically sized expanded allele are present in the post-mortem human HD brain, substantiating the extent of the tissue-specific instability observed and consistent with a major role in driving disease pathology.

Item Type:Conference or Workshop Item
Additional Information:Abstract published in Journal of Neurology, Neurosurgery and Psychiatry 89(S1):A1.
Glasgow Author(s) Enlighten ID:Chatzi, Ms Afroditi and Monckton, Professor Darren and Ciosi, Dr Marc
Authors: Ging, H., Nethisinghe, S., Chatzi, A., Ciosi, M., Monckton, D. G., and Giunti, P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology

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