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Investigation of the Influence of TBP CAG/CAA Repeats in Conjunction with HTT CAG Repeats on Huntington’s Disease Age at Onset in a Brazilian Sample

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Abstract

Huntington’s disease (HD) is a genetic neurodegenerative progressive and fatal disease characterized by motor disorder, cognitive impairment, and behavioral problems, caused by expanded repeats of CAG trinucleotides in the HTT gene. The aim of this study was to investigate the influence of TBP gene CAG/CAA repeats in conjunction with HTT gene CAG repeats, on the age at HD onset in Brazilian individuals. Individuals diagnosed as molecularly negative for HD presented 29–39 TBP CAG/CAA. Their most frequent allele had 36 repeats. In individuals diagnosed as molecularly positive for HD, a range of 25–40 TBP CAG/ CAA was found. The most frequent TBP allele had 38 repeats. We also conducted TBP direct Sanger sequencing of some samples which demonstrated other four TBP structures different from the basic TBP structure and others reported in the literature. The HTT expanded CAG and TBP CAG/CAA repeat sizes jointly explained 66% of the age at onset (AO) in our HD patients. The strongest variable in the model associated with AO was the number of expanded HTT CAG repeats. The difference between the association of HD AO with HTT expanded CAG together with TBP CAG/CAA and the association of HD AO with HTT expanded CAG was 0.001 (∆R2). Therefore, we found a weak association (0.1%) of TBP CAG/CAA repeats on HD AO, if any.

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Acknowledgements

Many thanks are due to the DNA Sequencing and Fragment Analysis Platform of IOC/FIOCRUZ/RJ and to the Centre for Molecular Medicine and Therapeutics (UBC), Vancouver, Canada, for the help with DNA sequencing. We also thank Dr. Suely Rodrigues dos Santos, Dr. Mariana Spitz, Dr. João Santos Pereira, and Dr. Luiz Felipe Vasconcellos for the referral of some patients, as well as the Brazilian Huntington’s Disease Association (ABH). Finally, we thank all the patients and their families for participating in this investigation.

Funding

This work was supported by CAPES (scholarships for I.S.S., T.A.A., and L.A.A. during their post-graduate studies), FAPERJ (grant no. E-26/010.000956/2016 to C.L.A.P), UNIRIO, and FINEP.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Biologia Molecular e Celular (PPGBMC), Universidade Federal do Estado do Rio de Janeiro (UNIRIO), Rio de Janeiro, RJ, Brazil

    Iane dos Santos da Silva & Carmen Lucia Antão Paiva

  2. Programa de Pós-Graduação em Neurologia, (UNIRIO), Rio de Janeiro, RJ, Brazil

    Thays Andrade Apolinário, Luciana de Andrade Agostinho & Carmen Lucia Antão Paiva

  3. Centro Universitário UNIFAMINAS, Muriae, Minas Gerais, Brazil

    Luciana de Andrade Agostinho

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  1. Iane dos Santos da Silva
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  2. Thays Andrade Apolinário
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  3. Luciana de Andrade Agostinho
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  4. Carmen Lucia Antão Paiva
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Contributions

Agostinho, Da Silva and Apolinário were responsible for the experiments. All authors contributed to the result analysis, statistical analysis, and wrote the manuscript. Agostinho and Paiva reviewed the final version of the article.

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Correspondence to Luciana de Andrade Agostinho.

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This study was approved by the HUGG Research Ethics Committee, Rio de Janeiro, Brazil, under the number CAAE 26387113.1.0000.5258.

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da Silva, I.d.S., Apolinário, T.A., de Andrade Agostinho, L. et al. Investigation of the Influence of TBP CAG/CAA Repeats in Conjunction with HTT CAG Repeats on Huntington’s Disease Age at Onset in a Brazilian Sample. J Mol Neurosci 72, 1116–1124 (2022). https://doi.org/10.1007/s12031-021-01938-z

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