All three MutL complexes are required for repeat expansion in a human stem cell model of CAG-repeat expansion mediated glutaminase deficiency.

Humans Glutaminase / genetics Trinucleotide Repeat Expansion / genetics Induced Pluripotent Stem Cells / metabolism MutL Proteins / genetics CRISPR-Cas Systems
GDPAG GLSD Glutaminase deficiency disorder Microsatellite instability Mismatch repair (MMR) Repeat expansion disease

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
14 Jun 2024
Historique:
received: 09 01 2024
accepted: 10 06 2024
medline: 15 6 2024
pubmed: 15 6 2024
entrez: 14 6 2024
Statut: epublish

Résumé

The Repeat Expansion Diseases (REDs) arise from the expansion of a disease-specific short tandem repeat (STR). Different REDs differ with respect to the repeat involved, the cells that are most expansion prone and the extent of expansion. Furthermore, whether these diseases share a common expansion mechanism is unclear. To date, expansion has only been studied in a limited number of REDs. Here we report the first studies of the expansion mechanism in induced pluripotent stem cells derived from a patient with a form of the glutaminase deficiency disorder known as Global Developmental Delay, Progressive Ataxia, And Elevated Glutamine (GDPAG; OMIM# 618412) caused by the expansion of a CAG-STR in the 5' UTR of the glutaminase (GLS) gene. We show that alleles with as few as ~ 120 repeats show detectable expansions in culture despite relatively low levels of R-loops formed at this locus. Additionally, using a CRISPR-Cas9 knockout approach we show that PMS2 and MLH3, the constituents of MutLα and MutLγ, the 2 mammalian MutL complexes known to be involved in mismatch repair (MMR), are essential for expansion. Furthermore, PMS1, a component of a less well understood MutL complex, MutLβ, is also important, if not essential, for repeat expansion in these cells. Our results provide insights into the factors important for expansion and lend weight to the idea that, despite some differences, the same mechanism is responsible for expansion in many, if not all, REDs.

Identifiants

DOI: 10.1038/s41598-024-64480-z PMID: 38877099
pubmed: 38877099
doi: 10.1038/s41598-024-64480-z
pii: 10.1038/s41598-024-64480-z
doi:

Substances chimiques

Glutaminase EC 3.5.1.2
MutL Proteins EC 3.6.1.3

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

13772

Subventions

Organisme : NIDDK NIH HHS
ID : DK057808
Pays : United States

Informations de copyright

© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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Auteurs

Bruce Hayward (B)

Section On Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

Daman Kumari (D)

Section On Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

Saikat Santra (S)

Birmingham Women's and Children's NHS Foundation Trust, Birmingham, B15 2TG, UK.

Clara D M van Karnebeek (CDM)

Emma Center for Personalized Medicine, Departments of Pediatrics and Human Genetics, Amsterdam Gastro-Enterology Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
United for Metabolic Diseases, Amsterdam, The Netherlands.

André B P van Kuilenburg (ABP)

Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.

Karen Usdin (K)

Section On Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA. karenu@nih.gov.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › All three MutL complexes are required for...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Amidohydrolases › Glutaminase › All three MutL complexes are required for...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Expansion de séquence répétée de l'ADN › Expansion de trinucléotide répété › All three MutL complexes are required for...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › All three MutL complexes are required for...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Protéines MutL › All three MutL complexes are required for...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Extinction de l'expression des gènes › Systèmes CRISPR-Cas › All three MutL complexes are required for...