Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease

Rosanna Beraldi; David K Meyerholz; Alexei Savinov; Attila D Kovács; Jill M Weimer; Jordan A Dykstra; Ryan D Geraets; David A Pearce

doi:10.1016/j.bbadis.2017.07.020

Back

Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease

Journal article

Open access

Peer reviewed

Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease

Rosanna Beraldi, David K Meyerholz, Alexei Savinov, Attila D Kovács, Jill M Weimer, Jordan A Dykstra, Ryan D Geraets and David A Pearce

Biochimica et biophysica acta. Molecular basis of disease, Vol.1863(11), pp.2862-2870

11/2017

DOI: 10.1016/j.bbadis.2017.07.020

PMCID: PMC5687068

PMID: 28746835

Files and links (1)

url

https://doi.org/10.1016/j.bbadis.2017.07.020View

Published (Version of record) Open Access

Abstract

Ataxia telangiectasia (AT) is a progressive multisystem autosomal recessive disorder caused by mutations in the AT-mutated (ATM) gene. Early onset AT in children is characterized by cerebellar degeneration, leading to motor impairment. Lung disease and cancer are the two most common causes of death in AT patients. Accelerated thymic involution may contribute to the cancer, and recurrent and/or chronic respiratory infections may be a contributing factor to lung disease in AT. AT patients have fertility issues, are highly sensitive to ionizing radiation and they present oculocutaneous telangiectasia. Current treatments only slightly ameliorate disease symptoms; therapy that alters or reverses the course of the disease has not yet been discovered. Previously, we have shown that ATM pigs, a novel model of AT, present with a loss of Purkinje cells, altered cerebellar cytoarchitecture and motor coordination deficits. ATM porcine model not only recapitulates the neurological phenotype, but also other multifaceted clinical features of the human disease. Our current study shows that ATM female pigs are infertile, with anatomical and functional signs of an immature reproductive system. Both male and female ATM pigs show abnormal thymus structure with decreased cell cycle and apoptosis markers in the gland. Moreover, ATM pigs have an altered immune system with decreased CD8 and increased natural killer and CD4 CD8 double-positive cells. Nevertheless, ATM pigs manifest a deficient IgG response after a viral infection. Based on the neurological and peripheral phenotypes, the ATM pig is a novel genetic model that may be used for therapeutic assessments and to identify pathomechanisms of this disease.

Purkinje Cells - metabolism

Swine - metabolism

Ataxia Telangiectasia Mutated Proteins - metabolism

Animals, Genetically Modified

Humans

Ataxia Telangiectasia - metabolism

Swine - genetics

Animals

Ataxia Telangiectasia - pathology

Ataxia Telangiectasia - genetics

Female

Ataxia Telangiectasia Mutated Proteins - genetics

Purkinje Cells - pathology

Disease Models, Animal

Details

Title: Subtitle: Genetic ataxia telangiectasia porcine model phenocopies the multisystemic features of the human disease
Creators: Rosanna Beraldi - Pediatric and Rare Diseases Group Sanford Research, Sioux Falls, SD 57104, USA; Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD 57105, USA
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Alexei Savinov - Diabetes Group Sanford Research, Sioux Falls, SD 57105, USA; Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD 57105, USA
Attila D Kovács - Pediatric and Rare Diseases Group Sanford Research, Sioux Falls, SD 57104, USA; Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD 57105, USA
Jill M Weimer - Pediatric and Rare Diseases Group Sanford Research, Sioux Falls, SD 57104, USA; Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD 57105, USA
Jordan A Dykstra - Pediatric and Rare Diseases Group Sanford Research, Sioux Falls, SD 57104, USA
Ryan D Geraets - Pediatric and Rare Diseases Group Sanford Research, Sioux Falls, SD 57104, USA; Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD 57105, USA
David A Pearce - Pediatric and Rare Diseases Group Sanford Research, Sioux Falls, SD 57104, USA; Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD 57105, USA. Electronic address: David.Pearce@SanfordHealth.org
Resource Type: Journal article
Publication Details: Biochimica et biophysica acta. Molecular basis of disease, Vol.1863(11), pp.2862-2870
DOI: 10.1016/j.bbadis.2017.07.020
PMID: 28746835
PMCID: PMC5687068
NLM abbreviation: Biochim Biophys Acta Mol Basis Dis
ISSN: 0925-4439
eISSN: 1879-260X
Grant note: R01 NS044310 / NINDS NIH HHS R01 NS036610 / NINDS NIH HHS P20 GM103548 / NIGMS NIH HHS R44 NS076075 / NINDS NIH HHS P20 GM103620 / NIGMS NIH HHS
Language: English
Date published: 11/2017
Academic Unit: Pathology
Record Identifier: 9984083880102771

Metrics

10 Record Views

7 Times Cited - Web of Science