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

Rosanna Beraldi; Chun-Hung Chan; Christopher S Rogers; Attila D Kovács; David K Meyerholz; Constantin Trantzas; Allyn M Lambertz; Benjamin W Darbro; Krystal L Weber; Katherine A M White; Richard V Rheeden; Michael C Kruer; Brian A Dacken; Xiao-Jun Wang; Bryan T Davis; Judy A Rohret; Jason T Struzynski; Frank A Rohret; Jill M Weimer; David A Pearce

doi:10.1093/hmg/ddv356

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

Journal article

Open access

Peer reviewed

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

Rosanna Beraldi, Chun-Hung Chan, Christopher S Rogers, Attila D Kovács, David K Meyerholz, Constantin Trantzas, Allyn M Lambertz, Benjamin W Darbro, Krystal L Weber, Katherine A M White, …

Human molecular genetics, Vol.24(22), pp.6473-6484

11/15/2015

DOI: 10.1093/hmg/ddv356

PMCID: PMC4614707

PMID: 26374845

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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.

Mutation

Ataxia Telangiectasia Mutated Proteins - metabolism

Genetic Association Studies

Animals, Genetically Modified

Humans

Male

Ataxia Telangiectasia - metabolism

Nuclear Transfer Techniques

Animals

Swine

Ataxia Telangiectasia - pathology

Ataxia Telangiectasia - genetics

Female

Ataxia Telangiectasia Mutated Proteins - genetics

Purkinje Cells - pathology

Disease Models, Animal

Details

Title: Subtitle: A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease
Creators: Rosanna Beraldi - Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA
Chun-Hung Chan - Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA
Christopher S Rogers - Exemplar Genetics, Sioux Center, IA 51250, USA
Attila D Kovács - Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Constantin Trantzas - ProtoKinetics, LLC, Peekskill, NY 10566, USA
Allyn M Lambertz - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Benjamin W Darbro - Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA and
Krystal L Weber - Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA
Katherine A M White - Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA
Richard V Rheeden - Department of Cytogenetics/Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA and
Michael C Kruer - Children's Health Research Center, Sanford Research, 2301 E. 60 Street North, Sioux Falls, SD 57104, USA
Brian A Dacken - Exemplar Genetics, Sioux Center, IA 51250, USA
Xiao-Jun Wang - Exemplar Genetics, Sioux Center, IA 51250, USA
Bryan T Davis - Exemplar Genetics, Sioux Center, IA 51250, USA
Judy A Rohret - Exemplar Genetics, Sioux Center, IA 51250, USA
Jason T Struzynski - Exemplar Genetics, Sioux Center, IA 51250, USA
Frank A Rohret - Exemplar Genetics, Sioux Center, IA 51250, USA
Jill M Weimer - 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 A Pearce - 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
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.24(22), pp.6473-6484
DOI: 10.1093/hmg/ddv356
PMID: 26374845
PMCID: PMC4614707
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: R44NS076075 / NINDS NIH HHS R01 NS082283 / NINDS NIH HHS K08 NS083739 / NINDS NIH HHS R44 NS076075 / NINDS NIH HHS P20 GM103620 / NIGMS NIH HHS 1R01NS082283 / NINDS NIH HHS
Language: English
Date published: 11/15/2015
Academic Unit: Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics
Record Identifier: 9984083282202771

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