Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome
(2024) In Scientific Reports 14(1).- Abstract
DNA mismatch repair (MMR) is thought to contribute to the onset and progression of Huntington disease (HD) by promoting somatic expansion of the pathogenic CAG nucleotide repeat in the huntingtin gene (HTT). Here we have studied constitutional HTT CAG repeat size in two cohorts of individuals with Lynch syndrome (LS) carrying heterozygous loss-of-function variants in the MMR genes MLH1 (n = 12/60; Lund cohort/Bochum cohort, respectively), MSH2 (n = 15/88), MSH6 (n = 21/23), and controls (n = 19/559). The sum of CAG repeats for both HTT alleles in each individual was calculated due to unknown segregation with the LS allele. In the larger Bochum cohort, the sum of CAG repeats was lower in the MLH1 subgroup compared to controls (MLH1 35.40... (More)
DNA mismatch repair (MMR) is thought to contribute to the onset and progression of Huntington disease (HD) by promoting somatic expansion of the pathogenic CAG nucleotide repeat in the huntingtin gene (HTT). Here we have studied constitutional HTT CAG repeat size in two cohorts of individuals with Lynch syndrome (LS) carrying heterozygous loss-of-function variants in the MMR genes MLH1 (n = 12/60; Lund cohort/Bochum cohort, respectively), MSH2 (n = 15/88), MSH6 (n = 21/23), and controls (n = 19/559). The sum of CAG repeats for both HTT alleles in each individual was calculated due to unknown segregation with the LS allele. In the larger Bochum cohort, the sum of CAG repeats was lower in the MLH1 subgroup compared to controls (MLH1 35.40 CAG repeats ± 3.6 vs. controls 36.89 CAG repeats ± 4.5; p = 0.014). All LS genetic subgroups in the Bochum cohort displayed lower frequencies of unstable HTT intermediate alleles and lower HTT somatic CAG repeat expansion index values compared to controls. Collectively, our results indicate that MMR gene haploinsufficiency could have a restraining impact on constitutional HTT CAG repeat size and support the notion that the MMR pathway is a driver of nucleotide repeat expansion diseases.
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- author
- Dalene Skarping, Karin LU ; Arning, Larissa ; Petersén, Åsa LU ; Nguyen, Huu Phuc and Gebre-Medhin, Samuel LU
- organization
- publishing date
- 2024-02
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- HTT CAG repeat size, Huntington disease, Lynch syndrome, Mismatch repair
- in
- Scientific Reports
- volume
- 14
- issue
- 1
- article number
- 4300
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:38383663
- scopus:85185682751
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-024-54277-5
- language
- English
- LU publication?
- yes
- id
- 8b858e28-0fca-40c6-b63c-11477bf3efd8
- date added to LUP
- 2024-03-14 15:02:15
- date last changed
- 2024-08-15 21:44:27
@article{8b858e28-0fca-40c6-b63c-11477bf3efd8, abstract = {{<p>DNA mismatch repair (MMR) is thought to contribute to the onset and progression of Huntington disease (HD) by promoting somatic expansion of the pathogenic CAG nucleotide repeat in the huntingtin gene (HTT). Here we have studied constitutional HTT CAG repeat size in two cohorts of individuals with Lynch syndrome (LS) carrying heterozygous loss-of-function variants in the MMR genes MLH1 (n = 12/60; Lund cohort/Bochum cohort, respectively), MSH2 (n = 15/88), MSH6 (n = 21/23), and controls (n = 19/559). The sum of CAG repeats for both HTT alleles in each individual was calculated due to unknown segregation with the LS allele. In the larger Bochum cohort, the sum of CAG repeats was lower in the MLH1 subgroup compared to controls (MLH1 35.40 CAG repeats ± 3.6 vs. controls 36.89 CAG repeats ± 4.5; p = 0.014). All LS genetic subgroups in the Bochum cohort displayed lower frequencies of unstable HTT intermediate alleles and lower HTT somatic CAG repeat expansion index values compared to controls. Collectively, our results indicate that MMR gene haploinsufficiency could have a restraining impact on constitutional HTT CAG repeat size and support the notion that the MMR pathway is a driver of nucleotide repeat expansion diseases.</p>}}, author = {{Dalene Skarping, Karin and Arning, Larissa and Petersén, Åsa and Nguyen, Huu Phuc and Gebre-Medhin, Samuel}}, issn = {{2045-2322}}, keywords = {{HTT CAG repeat size; Huntington disease; Lynch syndrome; Mismatch repair}}, language = {{eng}}, number = {{1}}, publisher = {{Nature Publishing Group}}, series = {{Scientific Reports}}, title = {{Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome}}, url = {{http://dx.doi.org/10.1038/s41598-024-54277-5}}, doi = {{10.1038/s41598-024-54277-5}}, volume = {{14}}, year = {{2024}}, }