Carbonic Anhydrase-Related Protein VIII Deficiency Is Associated With a Distinctive Lifelong Gait Disorder in Waddles Mice

Jiao, Yan; Yan, Jian; Zhao, Yu; Donahue, Leah Rae; Beamer, Wesley G.; Li, Xinmin; Roe, Bruce A.; LeDoux, Mark S.; Gu, Weikuan

doi:10.1534/genetics.105.044487

Cited by 116 publications

(148 citation statements)

References 18 publications

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“…As is the case for human gait disorders, distinct footprint patterns can be ascribed to lesions of specific neural subsystems in mice. Animals with cerebellar defects, for instance, oftentimes display considerable increases in both frontand hind-base widths (Wietholter et al, 1990;Jiao et al, 2005). In agreement with functional imaging studies, the increased hind-base width noted in hMT1 mice suggests that mutant torsinA may contribute to cerebellar dysfunction in humans with DYT1 dystonia (Carbon et al, 2004).…”

Section: Discussionsupporting

confidence: 60%

“…Footprint analysis along with digital surrogates have been used to examine gait alterations induced by striatal damage (Teunissen et al, 2001), genetic defects of Purkinje cells (Jiao et al, 2005), sensory neuropathy (Wietholter et al, 1990) and diffuse cerebral disease (McGavern et al, 1999). As is the case for human gait disorders, distinct footprint patterns can be ascribed to lesions of specific neural subsystems in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Adult (3-4 month) male hWT (n = 24) and hMT1 (n = 35) mice, along with WT (n = 20) ageand gender-matched littermate controls were used for quantitative analyses of motor function (Jiao et al, 2005). In addition, hMT1, hMT2, and hWT mice, including animals over one year of age, were routinely observed for evidence of dystonia during open field behavior.…”

Section: Behavioral Assessmentmentioning

confidence: 99%

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Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Zhao

DeCuypere

LeDoux

2008

Experimental Neurology

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A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90X). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA-and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Behavioral Assessmentmentioning

confidence: 99%

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Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Zhao

DeCuypere

LeDoux

2008

Experimental Neurology

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“…A mouse model (the 'waddles' mouse) develops ataxia, appendicular dystonia and abnormal ambulation as a result of a 19bp deletion in exon 8. 47 It is possible that atypical binding of UBR4 with calmodulin and/or ITPR1 may result in an abnormal calcium sensor system within the neuron and hence the development of ataxia. These reported findings highlight an interesting possible role of UBR 4 in the development of ataxia.…”

Section: Discussionmentioning

confidence: 99%

A novel locus for episodic ataxia:UBR4 the likely candidate

et al. 2013

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Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca 2 þ protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca 2 þ control within neuronal cells highlights its potential for a role in this form of EA.

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“…Examples include junctophilin 3 [7], carbonic anhydrase-related protein VIII (Car8) [8], and calretinin-deficient mice [9]. These mice are ataxic because of a deregulation of calcium homeostasis which impacts not only on Purkinje cell behavior but also upon other neurons of the cerebellar cortex [9].…”

mentioning

confidence: 99%

PTPRR, Cerebellum, and Motor Coordination

Schmitt

Bitoun

Manto³

2009

Cerebellum

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Tyrosine phosphorylation is a powerful mechanism of modulation for proliferation, differentiation, and functioning of neurons. The protein products of the neuronal mouse gene PTPRR are physiological regulators of mitogen-activated protein kinase (MAPK) activities. PTPRR −/− mice display deficits of motor coordination and balance skills. PTPRR gene orthologues are found in many vertebrates. Recent observations suggest that the human episodic ataxia 2 (EA2) and spinocerebellar ataxia types 6 (SCA6), 12 (SCA12), and 14 (SCA14) might be associated with impaired phosphorylation levels of cerebellum calcium channels and receptors. The concept that MAPK signaling is a key process in tuning synaptic plasticity in cerebellar circuits is now emerging, with numerous implications for understanding cerebellar functions and cerebellar disorders.

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Carbonic Anhydrase-Related Protein VIII Deficiency Is Associated With a Distinctive Lifelong Gait Disorder in Waddles Mice

Cited by 116 publications

References 18 publications

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice

A novel locus for episodic ataxia:UBR4 the likely candidate

PTPRR, Cerebellum, and Motor Coordination

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