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.
Highlights
Chédiak-Higashi syndrome (CHS) is a lethal disorder involving recurrent infections, coagulation defects, hypopigmentation, and progressive neurologic dysfunction[1,2,3,4,5]
We have previously shown that aged D2.Lyst mice exhibit a tremor phenotype that is dependent upon genetic background (Fig. 1) and is associated with a loss of cerebellar Purkinje cells (Fig. 2)[26]
To better define the nature of the tremor phenotype exhibited by Lyst-mutant mice, especially with respect to age of onset, we compared Lyst-mutants from both backgrounds using the CPSS27 for mouse models of cerebellar ataxia (Figs 3 and 4)
Summary
Chédiak-Higashi syndrome (CHS) is a lethal disorder involving recurrent infections, coagulation defects, hypopigmentation, and progressive neurologic dysfunction[1,2,3,4,5]. Regardless of when CHS is diagnosed, how it is treated, or its initial severity, all patients reported in the literature to date develop progressive neurologic deficits, including difficulty walking, loss of balance, and tremor[16,20,23]. For most patients these deficits become debilitating in their early 20’s23, independent of whether or not they have received bone-marrow transplantation. We apply behavioral assays for cerebellar disease combined with quantitative analysis of cellularity in the Purkinje layer to the study of B6-Lyst and D2.Lyst mice and test their ability to distinguish strain-dependent responses. Using quantitative reverse transcription PCR (RT-qPCR) to independently assess RNA expression levels, five genes are identified as leading candidates
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