Lynch Syndrome Genetics and Clinical Implications

Gastroenterology, Journal Year: 2023, Volume and Issue: 164(5), P. 783 - 799

Published: Jan. 24, 2023

Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in humans and accounts for some 3% unselected patients with colorectal or endometrial 10%-15% those DNA mismatch repair-deficient tumors. Previous studies have established genetic basis LS predisposition, but there been significant advances recently understanding molecular pathogenesis tumors, which has important implications clinical management. At same time, immunotherapy revolutionized treatment advanced cancers repair defects. We aim to review recent progress field discuss how accumulating epidemiologic, clinical, information contributed a more accurate complete picture LS, resulting genotype- immunologic subtype-specific strategies surveillance, prevention, treatment.

Language: Английский

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Cell-type-specific CAG repeat expansions and toxicity of mutant Huntingtin in human striatum and cerebellum

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(3), P. 383 - 394

Published: Jan. 30, 2024

Abstract Brain region-specific degeneration and somatic expansions of the mutant Huntingtin ( mHTT ) CAG tract are key features Huntington’s disease (HD). However, relationships among expansions, death specific cell types molecular events associated with these processes not established. Here, we used fluorescence-activated nuclear sorting (FANS) deep profiling to gain insight into properties human striatum cerebellum in HD control donors. arise at striatal medium spiny neurons (MSNs), cholinergic interneurons cerebellar Purkinje neurons, ATXN3 MSNs from SCA3 higher levels MSH2 MSH3 (forming MutSβ), which can inhibit nucleolytic excision slip-outs by FAN1. Our data support a model necessary but may be sufficient for identify transcriptional changes toxicity.

Language: Английский

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Uninterrupted CAG repeat drives striatum-selective transcriptionopathy and nuclear pathogenesis in human Huntingtin BAC mice

Neuron, Journal Year: 2022, Volume and Issue: 110(7), P. 1173 - 1192.e7

Published: Feb. 2, 2022

In Huntington's disease (HD), the uninterrupted CAG repeat length, but not polyglutamine predicts onset. However, underlying pathobiology remains unclear. Here, we developed bacterial artificial chromosome (BAC) transgenic mice expressing human mutant huntingtin (mHTT) with uninterrupted, and somatically unstable, repeats that exhibit progressive disease-related phenotypes. Unlike prior mHTT models stable, CAA-interrupted, polyglutamine-encoding repeats, BAC-CAG show robust striatum-selective nuclear inclusions transcriptional dysregulation resembling those in murine knockin HD patients. Importantly, striatal transcriptionopathy is significantly correlated their length length. Finally, among pathogenic entities originating from genomic transgenes only present or enriched model, somatic instability aggregation are best early-onset molecular pathogenesis locomotor sleep deficits, while RNA-associated pathologies repeat-associated non-AUG (RAN) translation may play less selective late roles, respectively.

Language: Английский

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Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 12, 2024

Abstract Huntington’s disease (HD) is a dominant neurological disorder caused by an expanded HTT exon 1 CAG repeat that lengthens huntingtin’s polyglutamine tract. Lowering mutant huntingtin has been proposed for treating HD, but genetic modifiers implicate somatic expansion as the driver of onset. We find branaplam and risdiplam, small molecule splice modulators lower promoting pseudoexon inclusion, also decrease unstable in engineered cell model. Targeted CRISPR-Cas9 editing shows this effect not due to lowering, pointing instead inclusion PMS1 . Homozygous heterozygous inactivation reduces expansion, supporting modifier HD potential target therapeutic intervention. Although modulation provides one strategy, genome-wide transcriptomics emphasize consideration cell-type specific effects polymorphic variation at both off-target sites.

Language: Английский

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Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 18, 2024

ABSTRACT Huntington’s disease (HD), due to expansion of a CAG repeat in HTT , is representative growing number disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers clinical landmarks somatic blood DNA reveal an underlying complexity cell-type specificity the mismatch repair-related processes influence timing. Differential capture non-DNA-repair gene by multiple measures cognitive motor dysfunction argues additionally for pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at 5’-UTR variant promotes without influencing HD, while, even after correcting uninterrupted length, synonymous sequence change end dramatically hastens onset signs increasing expansion. Our findings directly relevant therapeutic suppression HD related provide route define individual neuronal cell types contribute different phenotypes.

Language: Английский

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Huntington disease – Update on ongoing therapeutic developments and a look toward the future

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: 122, P. 106049 - 106049

Published: Feb. 15, 2024

Language: Английский

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Identification of genetic modifiers of Huntington’s disease somatic CAG repeat instability by in vivo CRISPR-Cas9 genome editing

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 9, 2024

Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative caused by CAG in

Language: Английский

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Msh3 and Pms1 Set Neuronal CAG-repeat Migration Rate to Drive Selective Striatal and Cortical Pathogenesis in HD Mice

Published: July 13, 2024

SUMMARY Modifiers of Huntington’s disease (HD) include mismatch repair (MMR) genes; however, their underlying disease-altering mechanisms remain unresolved. Knockout (KO) alleles for 9 HD GWAS modifiers/MMR genes were crossed to the Q140 Huntingtin (mHtt) knock-in mice probe such mechanisms. Four KO strongly ( Msh3 and Pms1 ) or moderately Msh2 Mlh1 rescue a triad adult-onset, striatal medium-spiny-neuron (MSN)-selective phenotypes: somatic Htt DNA CAG-repeat expansion, transcriptionopathy, mHtt protein aggregation. Comparatively, cortex also exhibits an analogous, but later-onset, pathogenic that is -dependent. Remarkably, Q140/homozygous Msh3-KO lacks visible aggregates in brain, even at advanced ages (20-months). Moreover, -deficiency prevents synaptic marker loss, astrogliosis, locomotor impairment mice. Purified MSN nuclei exhibit highly linear age-dependent repeat expansion (i.e. migration), with modal-CAG increasing +8.8 repeats/month (R 2 =0.98). This rate reduced 2.3 0.3 heterozygous homozygous alleles, respectively. Our study defines thresholds below which there are no detectable nuclear neuropil aggregates. Mild transcriptionopathy can still occur stabilized 140-CAG repeats, majority transcriptomic changes due expansion. analysis reveals 479 expression levels correlated length MSNs. Thus, our mechanistically connects selective neuronal vulnerability HD, set migration drive repeat-length dependent pathogenesis; provides preclinical platform targeting these suppression across brain regions. One Sentence Summary genetic drivers sequential cortical pathogenesis by mediating vulnerable neurons.

Language: Английский

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In vivo CRISPR–Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington’s disease

Nature Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Huntington's disease, one of more than 50 inherited repeat expansion disorders1, is a dominantly neurodegenerative disease caused by CAG in HTT2. Inherited length the primary determinant age onset, with human genetic studies underscoring that driven length-dependent propensity to further expand brain3–9. Routes slowing somatic expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably mismatch pathway, modify mouse models10. To identify novel modifiers we used CRISPR–Cas9 editing knock-in mice enable vivo screening expansion-modifier candidates at scale. This included testing onset modifier genes emerging from genome-wide association as well interactions between providing insight into pathways underlying and potential therapeutic targets. A strategy identifies new contribute disease.

Language: Английский

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Distinct mismatch-repair complex genes set neuronal CAG-repeat expansion rate to drive selective pathogenesis in HD mice

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Highlights•Mismatch-repair genes drive striatal and cortical neuronal pathogenesis in HD mice•Linear rate of CAG expansion neurons is dependent on Msh3 Pms1•Somatic elicits repeat-length -threshold-dependent pathologies•Msh3 deficiency corrects synaptic, astrocytic, locomotor defects miceSummaryHuntington's disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to remain unclear. Here, we genetically tested 9 genome-wide association study (GWAS)/MMR mutant Huntingtin (mHtt) mice with 140 inherited repeats (Q140). Knockout (KO) encoding a distinct MMR complex either strongly (Msh3 Pms1) or moderately (Msh2 Mlh1) rescues phenotypes early onset medium-spiny (MSNs) late the neurons: somatic CAG-repeat expansion, transcriptionopathy, mHtt aggregation. ameliorates open-chromatin dysregulation Q140 neurons. Mechanistically, fast linear modal-CAG-repeat MSNs (8.8 repeats/month) drastically reduced stopped by mutants. Pms1 prevents aggregation keeping MSN length below 150. Importantly, mice. Thus, CAG-expansion rates HD-vulnerable elicit repeat-length/threshold-dependent, selective, progressive vivo.Graphical abstract

Language: Английский

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