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| Status |
Public on Jun 01, 2024 |
| Title |
A murine model lacking Lyst recapitulates Chediak-Higashi syndrome with an earlier-onset neurodegenerative phenotype |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the lysosomal trafficking regulator (LYST) gene, characterized by partial oculocutaneous albinism, bleeding diathesis, immune deficiency, and progressive neurodegeneration. We generated a Lyst knockout model (ΔLYST-B6) in which to accurately study pathophysiology seen in patients. Here we show the ΔLYST-B6 model faithfully recapitulates characteristic features of CHS, including neurological manifestations at 6 months of age with associated progressive loss of Purkinje cells. Transcriptomic and lipidomic analyses of ΔLYST-B6 brain tissue reveals numerous differentially expressed genes and lipids in the cerebellum of 18-month-old ΔLYST-B6 mice suggesting progressive cerebellar decline and microglial involvement. Immunofluorescence studies implicate a plausible role of Bergmann glia in the pathology of CHS. Our findings demonstrate that the ΔLYST-B6 model recapitulates key features of the human CHS phenotype, including CHS-associated neurodegeneration, and provides a reliable model in which to study the function of LYST and explore future therapies for CHS.
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| Overall design |
A knockout mouse model (ΔLYST-B6) lacking a functional murine Lyst homologue was generated by deleting exons 4-53 using CRISPR/Cas9 gene editing on the C57BL/6J genetic background. To characterize the neurological phenotype of ΔLYST-B6 mice, brain tissues (cerebellum and cortex) were collected from 3- and 18-month-old wildtype and ΔLYST-B6 mice.
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| Citation missing |
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| Submission date |
Apr 29, 2024 |
| Last update date |
Jun 12, 2024 |
| Contact name |
May Christine V Malicdan |
| E-mail(s) |
maychristine.malicdan@nih.gov
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| Organization name |
National Institutes of Health
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| Department |
National Human Genome Research Institute
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| Lab |
Undiagnosed Diseases Program Translational Lab
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| Street address |
5625 Fisher's Ln
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| City |
Rockville |
| State/province |
MD |
| ZIP/Postal code |
20852 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (24)
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| GSM8241382 |
Lyst-Knockout mouse 19351, brain tissue (cerebellum), replicate 1 |
| GSM8241383 |
Lyst-Knockout mouse 19351, brain tissue (cerebellum), replicate 2 |
| GSM8241384 |
Lyst-Knockout mouse 19351, brain tissue (cerebellum), replicate 3 |
| GSM8241385 |
Lyst-Knockout mouse 19351, brain tissue (cortex), replicate 1 |
| GSM8241386 |
Lyst-Knockout mouse 19351, brain tissue (cortex), replicate 2 |
| GSM8241387 |
Lyst-Knockout mouse 19351, brain tissue (cortex), replicate 3 |
| GSM8241388 |
Lyst-Knockout mouse 390, brain tissue (cerebellum), replicate 1 |
| GSM8241389 |
Lyst-Knockout mouse 390, brain tissue (cerebellum), replicate 2 |
| GSM8241390 |
Lyst-Knockout mouse 390, brain tissue (cortex), replicate 1 |
| GSM8241391 |
Lyst-Knockout mouse 390, brain tissue (cortex), replicate 2 |
| GSM8241392 |
Lyst-Knockout mouse 397, brain tissue (cerebellum), replicate 1 |
| GSM8241393 |
Lyst-Knockout mouse 397, brain tissue (cortex), replicate 1 |
| GSM8241394 |
Wildtype mouse 19311, brain tissue (cerebellum), replicate 1 |
| GSM8241395 |
Wildtype mouse 19311, brain tissue (cortex), replicate 1 |
| GSM8241396 |
Wildtype mouse 19352, brain tissue (cerebellum), replicate 1 |
| GSM8241397 |
Wildtype mouse 19352, brain tissue (cerebellum), replicate 2 |
| GSM8241398 |
Wildtype mouse 19352, brain tissue (cortex), replicate 1 |
| GSM8241399 |
Wildtype mouse 19352, brain tissue (cortex), replicate 2 |
| GSM8241400 |
Wildtype mouse 391, brain tissue (cerebellum), replicate 1 |
| GSM8241401 |
Wildtype mouse 391, brain tissue (cortex), replicate 1 |
| GSM8241402 |
Wildtype mouse 397, brain tissue (cerebellum), replicate 1 |
| GSM8241403 |
Wildtype mouse 397, brain tissue (cerebellum), replicate 2 |
| GSM8241404 |
Wildtype mouse 397, brain tissue (cortex), replicate 1 |
| GSM8241405 |
Wildtype mouse 397, brain tissue (cortex), replicate 2 |
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| Relations |
| BioProject |
PRJNA1105982 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE266142_Lyst_KO_Mice_DESeq2_All_Samples_Expression.csv.gz |
837.2 Kb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
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