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other·preclinical research, neurology, biomedical research, pediatrics·PMC10360390

A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects

Human Molecular Genetics · 15 authors, 26 centres

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TL;DR

Researchers generated and characterized the first knock-in mouse model of ATR-X syndrome carrying the most common patient mutation (R246C/R245C). The mice recapitulated several features of the human disorder, including craniofacial defects, microcephaly, reduced body size, and impaired neurological function.

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This preclinical study generated the first patient-mutation knock-in mouse model of ATR-X syndrome, carrying the R246C (R245C in mouse) missense mutation in the ATRX chromatin-binding domain. Morphological characterization revealed reduced body size, reduced brain weight, and a shortened snout phenotype. Neurobehavioural testing using the Barnes Maze, Social Interaction test, and contextual fear conditioning demonstrated impaired spatial memory, novelty preference, and fear memory. Cellular analysis showed reduced dendritic length and branching in neurons. Notably, alpha-thalassemia, genital abnormalities, and muscle hypotonia seen in patients were not recapitulated, attributed to species differences in the mouse locus and mutation location. The ATRX[R245C] mutant protein rescued neuronal death seen in ATRX-null forebrains.

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other

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preclinical research

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ORIGINAL PAPER

PMC10360390

A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects

Human Molecular Genetics

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ABSTRACT

Abstract ATRX is a chromatin remodelling ATPase that is involved in transcriptional regulation, DNA damage repair and heterochromatin maintenance. It has been widely studied for its role in ALT-positive cancers, but its role in neurological function remains elusive. Hypomorphic mutations in the X-linked ATRX gene cause a rare form of intellectual disability combined with alpha-thalassemia called ATR-X syndrome in hemizygous males. Clinical features also include facial dysmorphism, microcephaly, short stature, musculoskeletal defects and genital abnormalities. As complete deletion of ATRX in mice results in early embryonic lethality, the field has largely relied on conditional knockout models to assess the role of ATRX in multiple tissues. Given that null alleles are not found in patients, a more patient-relevant model was needed. Here, we have produced and characterized the first patient mutation knock-in model of ATR-X syndrome, carrying the most common causative mutation, R246C. This is one of a cluster of missense mutations located in the chromatin-binding domain and disrupts its function. The knock-in mice recapitulate several aspects of the patient disorder, including craniofacial defects, microcephaly, reduced body size and impaired neurological function. They provide a powerful model for understanding the molecular mechanisms underlying ATR-X syndrome and testing potential therapeutic strategies.

CITATION EXPORT

Rebekah Tillotson, Keqin Yan, Julie Ruston et al.. A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects. Human Molecular Genetics. (2023). https://doi.org/10.1093/hmg/ddad075

AUTHORS

15 · 26 CENTRES

Rebekah Tillotson, Keqin Yan, Julie Ruston, Taylor DeYoung, Alex Córdova, Valérie Turcotte-Cardin, Yohan Yee, Christine Taylor, Shagana Visuvanathan, Christian Babbs, Evgueni A Ivakine, John G Sled, Brian J Nieman, David J Picketts, Monica J Justice

1 Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
2 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital/Headley Way, Oxford OX3 9DS, UK
3 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
4 Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
5 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
6 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
7 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
8 Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
9 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
10 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
11 Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
12 Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
13 MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital/Headley Way, Oxford OX3 9DS, UK
14 Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
15 Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
16 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
17 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
18 Translational Medicine Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
19 Mouse Imaging Centre, The Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
20 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
21 Translational Medicine Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
22 Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
23 Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada
24 Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
25 Genetics and Genome Biology Program, The Hospital for Sick Children, The Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada
26 Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada