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Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome

Dalene Skarping, Karin LU ; Arning, Larissa ; Petersén, Åsa LU ; Nguyen, Huu Phuc and Gebre-Medhin, Samuel LU (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
; ; ; and
organization
publishing date
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
2024-04-25 11:46:24
@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}},
}