RGD Reference Report - Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage. - Rat Genome Database

Send us a Message

Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage.

Authors: Quek, Hazel  Luff, John  Cheung, KaGeen  Kozlov, Sergei  Gatei, Magtouf  Lee, C Soon  Bellingham, Mark C  Noakes, Peter G  Lim, Yi Chieh  Barnett, Nigel L  Dingwall, Steven  Wolvetang, Ernst  Mashimo, Tomoji  Roberts, Tara L  Lavin, Martin F 
Citation: Quek H, etal., J Leukoc Biol. 2017 Apr;101(4):927-947. doi: 10.1189/jlb.4VMA0716-316R. Epub 2016 Nov 28.
RGD ID: 12879393
Pubmed: PMID:27895165   (View Abstract at PubMed)
DOI: DOI:10.1189/jlb.4VMA0716-316R   (Journal Full-text)

Mutations in the ataxia-telangiectasia (A-T)-mutated (ATM) gene give rise to the human genetic disorder A-T, characterized by immunodeficiency, cancer predisposition, and neurodegeneration. Whereas a series of animal models recapitulate much of the A-T phenotype, they fail to present with ataxia or neurodegeneration. We describe here the generation of an Atm missense mutant [amino acid change of leucine (L) to proline (P) at position 2262 (L2262P)] rat by intracytoplasmic injection (ICSI) of mutant sperm into oocytes. Atm-mutant rats (Atm(L2262P/L2262P) ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with Atm(+/+) Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors. Closer examination revealed the presence of both dsDNA and ssDNA in the cytoplasm of cells in the hippocampus, cerebellum, and spinal cord of Atm(L2262P/L2262P) rats. Significantly increased levels of IFN-ß and IL-1ß in all 3 tissues were indicative of DNA damage induction of the type 1 IFN response. This was further supported by NF-κB activation, as evidenced by p65 phosphorylation (P65) and translocation to the nucleus in the spinal cord and parahippocampus. Other evidence of neuroinflammation in the brain and spinal cord was the loss of motor neurons and the presence of increased activation of microglia. These data provide support for a proinflammatory phenotype that is manifested in the Atm mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ATMHumandisease of cellular proliferation  ISOAtm (Rattus norvegicus) RGD 
AtmMousedisease of cellular proliferation  ISOAtm (Rattus norvegicus) RGD 
AtmRatdisease of cellular proliferation  IMP  RGD 
Atmm1KyoRatdisease of cellular proliferation  IMP  RGD 
F344-Atmm1KyoRatdisease of cellular proliferation  IMP  RGD 
ATMHumaninfertility  ISOAtm (Rattus norvegicus)DNA:missense mutation:cds:RGD 
AtmMouseinfertility  ISOAtm (Rattus norvegicus) RGD 
AtmRatinfertility  IMP DNA:missense mutation:cds:RGD 
Atmm1KyoRatinfertility  IMP  RGD 
F344-Atmm1KyoRatinfertility  IMP  RGD 
ATMHumanlymphoma  ISOAtm (Rattus norvegicus)DNA:missense mutation:cds:RGD 
AtmMouselymphoma  ISOAtm (Rattus norvegicus) RGD 
AtmRatlymphoma  IMP DNA:missense mutation:cds:RGD 
Atmm1KyoRatlymphoma  IMP  RGD 
F344-Atmm1KyoRatlymphoma  IMP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
AtmRatpositive regulation of DNA catabolic process  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)
Atmm1Kyo  (ATM serine/threonine kinase; ENU induced mutant 1, Kyo)

Genes (Mus musculus)
Atm  (ataxia telangiectasia mutated)

Genes (Homo sapiens)
ATM  (ATM serine/threonine kinase)

F344-Atmm1Kyo  (Atm missense rats)

Additional Information