Abstract
ABSTRACTThe shaker rat is an X-linked recessive spontaneous model of progressive Purkinje cell (PC) degeneration exhibiting a shaking ataxia and wide stance. Generation of Wistar Furth (WF)/Brown Norwegian (BN) F1 hybrids and genetic mapping of F2 sib-sib offspring using polymorphic markers narrowed the candidate gene region to 26 Mbp denoted by the last recombinant genetic marker DXRat21 at 133 Mbp to qter (the end of the long arm). In the WF background, the shaker mutation has complete penetrance, results in a stereotypic phenotype and there is a narrow window for age of disease onset; by contrast, the F2 hybrid phenotype was more varied, with a later age of onset and likely non-penetrance of the mutation. By deep RNA-sequencing, five variants were found in the candidate region; four were novel without known annotation. One of the variants caused an arginine (R) to cysteine (C) change at codon 35 of the ATPase, Ca2+ transporting, plasma membrane 3 (Atp2b3) gene encoding PMCA3 that has high expression in the cerebellum. The variant was well supported by hundreds of overlapping reads, and was found in 100% of all affected replicas and 0% of the wild-type (WT) replicas. The mutation segregated with disease in all affected animals and the amino acid change was found in an evolutionarily conserved region of PMCA3. Despite strong genetic evidence for pathogenicity, in vitro analyses of PMCA3R35C function did not show any differences to WT PMCA3. Because Atp2b3 mutation leads to congenital ataxia in humans, the identified Atp2b3 missense change in the shaker rat presents a good candidate for the shaker rat phenotype based on genetic criteria, but cannot yet be considered a definite pathogenic variant owing to lack of functional changes.
Highlights
Hereditary ataxias in humans comprise a diverse group of diseases that affect the cerebellum and various other regions of the nervous system
In a different rodent model of cerebellar ataxia, that the expressions of Calb1, Pcp2 and Grid2, as well as that of some other genes highly expressed in Purkinje cell (PC), significantly reduce as the disease phenotype progresses (Dansithong et al, 2015; Hansen et al, 2013)
Wider hind-limb stance for carrier females versus WT rats was attributed to mild loss of PCs, as determined by immunofluorescent staining for calbindin (Clark et al, 2000; Tolbert et al, 1995)
Summary
Hereditary ataxias in humans comprise a diverse group of diseases that affect the cerebellum and various other regions of the nervous system. The classification of these disorders is complex owing to heterogeneity in clinical signs, age of onset, disease progression and. We describe the genetic analysis of the shaker rat, a model of Purkinje cell (PC) degeneration. This mutant arose spontaneously and was observed in Sprague Dawley (SD) outbred stock in 1991 at Saint Louis University, first described by La Regina et al (1992), and the phenotype of whole-body tremor, ataxia and wide stance designated as ‘shaker’. The shaker trait was reported as an X-linked recessive trait
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