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Hum Mol Genet. 2015 Nov 15;24(22):6473-84. doi: 10.1093/hmg/ddv356. Epub 2015 Sep 15.

A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease.

Author information

1
Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA.
2
Exemplar Genetics, Sioux Center, IA 51250, USA.
3
Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
4
ProtoKinetics, LLC, Peekskill, NY 10566, USA.
5
Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA and.
6
Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA, School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA.
7
Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA, School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA david.pearce@sanfordhealth.org.

Abstract

Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions.

PMID:
26374845
PMCID:
PMC4614707
DOI:
10.1093/hmg/ddv356
[Indexed for MEDLINE]
Free PMC Article

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