Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction

Adam Hedberg-Buenz; Laura M Dutca; Demelza R Larson; Kacie J Meyer; Dana A Soukup; Carly J van der Heide; Hannah E Mercer; Kai Wang; Michael G Anderson

doi:10.1038/s41598-019-42159-0

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Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction

Journal article

Open access

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Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction

Adam Hedberg-Buenz, Laura M Dutca, Demelza R Larson, Kacie J Meyer, Dana A Soukup, Carly J van der Heide, Hannah E Mercer, Kai Wang and Michael G Anderson

Scientific reports, Vol.9(1), pp.6752-6752

05/01/2019

DOI: 10.1038/s41598-019-42159-0

PMCID: PMC6494809

PMID: 31043676

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Abstract

Chédiak-Higashi syndrome (CHS) is a lethal disorder caused by mutations in the LYST gene that involves progressive neurologic dysfunction. Lyst-mutant mice exhibit neurologic phenotypes that are sensitive to genetic background. On the DBA/2J-, but not on the C57BL/6J-background, Lyst-mutant mice exhibit overt tremor phenotypes associated with loss of cerebellar Purkinje cells. Here, we tested whether assays for ataxia could measure this observed strain-dependency, and if so, establish parameters for empowering phenotype- and candidate-driven approaches to identify genetic modifier(s). A composite phenotypic scoring system distinguished phenotypes in Lyst-mutants and uncovered a previously unrecognized background difference between wild-type C57BL/6J and DBA/2J mice. Accelerating rotarod performance also distinguished phenotypes in Lyst-mutants, but at more advanced ages. These results establish that genetic background, Lyst genotype, and age significantly influence the severity of CHS-associated neurologic deficits. Purkinje cell quantifications likewise distinguished phenotypes of Lyst-mutant mice, as well as background differences between wild-type C57BL/6J and DBA/2J mice. To aid identification of potential genetic modifier genes causing these effects, we searched public datasets for cerebellar-expressed genes that are differentially expressed and/or contain potentially detrimental genetic variants. From these approaches, Nos1, Prdx2, Cbln3, Gnb1, Pttg1 were confirmed to be differentially expressed and leading candidates.

Animals

Cerebellar Ataxia - etiology

Cerebellar Ataxia - pathology

Chediak-Higashi Syndrome - complications

Disease Models, Animal

Female

Genotype

Mice

Mice, Inbred C57BL

Mice, Inbred DBA

Mutation

Nervous System Diseases - etiology

Nervous System Diseases - pathology

Phenotype

Details

Title: Subtitle: Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction
Creators: Adam Hedberg-Buenz - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, 52242, USA
Laura M Dutca - Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, 52242, USA
Demelza R Larson - Biology Department, College of St. Benedict & St. John's University, Collegeville, Minnesota, 56321, USA
Kacie J Meyer - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, 52242, USA
Dana A Soukup - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, 52242, USA
Carly J van der Heide - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, 52242, USA
Hannah E Mercer - Department of Molecular Physiology and Biophysics, The University of Iowa, Iowa City, IA, 52242, USA
Kai Wang - Department of Biostatistics, The University of Iowa, Iowa City, IA, 52242, USA
Michael G Anderson - Department of Ophthalmology and Visual Sciences, The University of Iowa, Iowa City, IA, 52242, USA. michael-g-anderson@uiowa.edu
Resource Type: Journal article
Publication Details: Scientific reports, Vol.9(1), pp.6752-6752
DOI: 10.1038/s41598-019-42159-0
PMID: 31043676
PMCID: PMC6494809
NLM abbreviation: Sci Rep
ISSN: 2045-2322
eISSN: 2045-2322
Grant note: P30 EY025580 / NEI NIH HHS IK2 RX002003 / RRD VA T32 GM007337 / NIGMS NIH HHS T32 DK112751 / NIDDK NIH HHS T32DK112751 / U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER) I01 RX001481 / RRD VA R21 EY029609 / NEI NIH HHS R01 EY017673 / NEI NIH HHS
Language: English
Date published: 05/01/2019
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Biostatistics; Ophthalmology and Visual Sciences
Record Identifier: 9984172264802771

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