SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia

Kimura, Mari; Yabe, Ichiro; Hama, Yuka; Eguchi, Katsuki; Ura, Shigehisa; Tsuzaka, Kazufumi; Tsuji, Shoji; Sasaki, Hidenao

doi:10.1038/jhg.2017.51

Cited by 25 publications

(21 citation statements)

References 5 publications

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“…Post-mortem histological examination revealed cerebellar atrophy in association with a prominent Purkinje cell loss [64]. A heterozygous single point mutation in the CACNA1G gene which causes an arginine-to-histidine (p.Arg1715His) change in the S4 voltage-sensing region of the T-type voltage-gated Ca 2+ channel protein Ca(v)3.1 has concurrently been associated to SCA42 in ten families [64][65][66][67]. T-type Ca 2+ channels are widely expressed in the brain, including the thalamus, hippocampus, neocortex, and cerebellum [68].…”

Section: Mutations In the Cacna1g Genementioning

confidence: 99%

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Prestori

Moccia

D’Angelo

2019

IJMS

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Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells. Ca2+ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca2+ channels, Ca2+-dependent kinases and phosphatases, and Ca2+-binding proteins to tightly maintain Ca2+ homeostasis and regulate physiological Ca2+-dependent processes. Abnormal Ca2+ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca2+ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

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Section: Mutations In the Cacna1g Genementioning

confidence: 99%

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Prestori

Moccia

D’Angelo

2019

IJMS

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“… 1 These genetic diseases are characterized by autosomal dominant inheritance with approximately 44 known subtypes. Recently, dominant mutations in the CACNA1G gene, encoding the voltage-gated calcium channel Ca V 3.1, have been linked to SCA42 in French 2 and Japanese 3 , 4 families. SCA42 prevalence elsewhere in the world has yet to be documented.…”

mentioning

confidence: 99%

Expanding the global prevalence of spinocerebellar ataxia type 42

et al. 2018

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“…There is variable age at onset (range 9- >78 years) and slow progression of the disease. We reviewed the clinical data in the CACNA1G families for the characteristic signs of SCA42 including ataxia, gait instability and ocular signs [48-50]. None of the individuals with ET in these families exhibited these problems, suggesting that these families do not have SCA.…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

Odgerel

Hernández

Park

et al. 2018

Preprint

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Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns. In ET families with Mendelian inheritance patterns, WGS may lead to gene identification where WES analysis failed to identify the causative variant due to incomplete coverage of the entire coding region of the genome. Alternatively, in ET families with complex disease inheritance patterns with gene x gene and gene x environment interactions enrichment of functional rare coding and non-coding variants may explain the heritability of ET. We performed WGS in eight ET families (n=40 individuals) enrolled in the Family Study of Essential Tremor. The analysis included filtering WGS data based on allele frequency in population databases, rare variant classification and association testing using the Mixed-Model Kernel Based Adaptive Cluster (MM-KBAC) test and prioritization of candidate genes identified within families using phenolyzer. WGS analysis identified candidate genes for ET in 5/8 (62.5%) of the families analyzed. WES analysis in a subset of these families in our previously published study failed to identify candidate genes. In one family, we identified a deleterious and damaging variant (c.1367G>A, p.(Arg456Gln)) in the candidate gene, CACNA1G, which encodes the pore forming subunit of T-type Ca(2+) channels, CaV3.1, and is expressed in various motor pathways and has been previously implicated in neuronal autorhythmicity and ET. Other candidate genes identified include SLIT3 (family D), which encodes an axon guidance molecule and in three families, phenolyzer prioritized genes that are associated with hereditary neuropathies (family A, KARS, family B, KIF5A and family F, NTRK1). This work has identified candidate genes and pathways for ET that can now be prioritized for functional studies.

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SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia

Cited by 25 publications

References 5 publications

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Expanding the global prevalence of spinocerebellar ataxia type 42

Whole Genome Sequencing and Rare Variant Analysis in Essential Tremor Families

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