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

Autor: Dalene Skarping K; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.; Department of Clinical Genetics and Pathology, Office for Medical Service, 221 85, Lund, Sweden.; Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden., Arning L; Department of Human Genetics, Faculty of Medicine, Ruhr University Bochum, Universitätsstr. 150, 44801, Bochum, Germany., Petersén Å; Translational Neuroendocrine Research Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden., Nguyen HP; Department of Human Genetics, Faculty of Medicine, Ruhr University Bochum, Universitätsstr. 150, 44801, Bochum, Germany. Huu.Nguyen-r7w@ruhr-uni-bochum.de., Gebre-Medhin S; Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. samuel.gebre-medhin@med.lu.se.; Department of Clinical Genetics and Pathology, Office for Medical Service, 221 85, Lund, Sweden. samuel.gebre-medhin@med.lu.se.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Feb 21; Vol. 14 (1), pp. 4300. Date of Electronic Publication: 2024 Feb 21.
DOI: 10.1038/s41598-024-54277-5
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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