RGD Reference Report - Platelet and myeloid cell phenotypes in a rat model of Fabry disease. - Rat Genome Database

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Platelet and myeloid cell phenotypes in a rat model of Fabry disease.

Authors: Kanack, Adam J  Aoki, Kazuhiro  Tiemeyer, Michael  Dahms, Nancy M 
Citation: Kanack AJ, etal., FASEB J. 2021 Aug;35(8):e21818. doi: 10.1096/fj.202001727RR.
RGD ID: 401976418
Pubmed: PMID:34320241   (View Abstract at PubMed)
PMCID: PMC8341388   (View Article at PubMed Central)
DOI: DOI:10.1096/fj.202001727RR   (Journal Full-text)

Fabry disease results from a deficiency of the lysosomal enzyme ⍺-Galactosidase-A (⍺-Gal A) and is estimated to occur in approximately 1:4100 live births. Characteristic of the disease is the accumulation of α-Gal-A substrates, primarily the glycosphingolipids (GSLs) globotriaosylceramide and globotriaosylsphingosine. Thrombotic events are a significant concern for Fabry patients, with strokes contributing to a significant decrease in overall lifespan. Currently, the mechanisms underlying the increased risk of thrombotic events experienced by Fabry patients are incompletely defined. Using a rat model of Fabry disease, we provide an improved understanding of the mechanisms linking GSL accumulation to thrombotic risk. We found that ⍺-Gal A-deficient rats accumulate myeloid-derived leukocytes at sites of GSL accumulation, including in the bone marrow and circulation, and that myeloid-derived leukocyte and megakaryocyte populations were prominent among cell types that accumulated GSLs. In the circulation, ⍺-Gal A-deficient rats had increases in cytokine-producing cell types and a corresponding elevation of pro-inflammatory cytokines. Lastly, circulating platelets from ⍺-Gal A-deficient rats accumulated a similar set of ⍺-Galactosidase-A substrates as was observed in megakaryocytes in the bone marrow, and exhibited increased platelet binding to fibrinogen in microfluidic and flow cytometric assays.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Fabry disease MODELIMP 401976418compared to wild typeRGD 
Fabry disease  ISOGla (Rattus norvegicus)401976418; 401976418compared to wild typeRGD 
Fabry disease  IMP 401976418; 401976418compared to wild typeRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
glycosphingolipid catabolic process  IMP 401976418 RGD 
platelet activation  IMP 401976418 RGD 
platelet aggregation  IMP 401976418 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal circulating cytokine level  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal glycosphingolipid level  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal lysosome morphology  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal megakaryocyte progenitor cell morphology  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal myeloid cell number  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal myeloid leukocyte morphology  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal platelet activation  IMP 401976418 RGD 
abnormal platelet aggregation  IMP 401976418 RGD 
abnormal platelet morphology  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal reticulocyte cell number  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
abnormal reticulocyte morphology  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
decreased mean corpuscular hemoglobin  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
decreased mean corpuscular volume  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
increased circulating interleukin-17 level  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
increased circulating tumor necrosis factor level  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
increased erythrocyte cell number  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
increased macrophage cell number  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
lysosomal protein accumulation  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
thrombocytosis  IMP 401976418; 401976418; 401976418compared to wild typeRGD 
Objects Annotated

Genes (Rattus norvegicus)
Gla  (galactosidase, alpha)
Glaem2Mcwi  (galactosidase, alpha; CRISPR/Cas9 system induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Gla  (galactosidase, alpha)

Genes (Homo sapiens)
GLA  (galactosidase alpha)

Strains
DA-Glaem2Mcwi  (NA)


Additional Information