Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

Watson, Lauren M.; Bamber, Emily R.; Schnekenberg, Ricardo Parolin; Williams, Jonathan; Bettencourt, Conceição; Lickiss, Jennifer; Jayawant, Sandeep; Fawcett, Katherine A.; Clokie, Samuel; Wallis, Yvonne; Clouston, Penny; Sims, David; Houlden, Henry; Becker, Esther B. E.; Németh, Andrea H.

doi:10.1016/j.ajhg.2017.08.005

Cited by 67 publications

(43 citation statements)

References 43 publications

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“…• Glutamate metabotropic receptor 1 (Grm1)-Grm1 has been associated with the alterations in synaptic plasticity and glutamate disturbances that result in neuronal overexcitation, a hallmark of epilepsy (46,55). Grm1 mutations can also cause spinocerebellar ataxia type 44, a genetic disease that can present with seizures.…”

Section: Discussionmentioning

confidence: 99%

“…We were particularly interested that BDNF, Calcium Voltage-Gated Channel Auxiliary Subunit Beta 4 (Cacnb4), Gabrg2, Grm1, Jak1/2, and Sodium Voltage-Gated Channel Alpha Subunit 1(Scn1a) were on the list. They have all been associated with epilepsy models and with human mutations in epilepsy patients (33,(44)(45)(46).…”

Section: Comparison Of Degs With Chip-seq Datasetsmentioning

confidence: 99%

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Transcriptomic analysis of the BDNF-induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression

Cogswell

et al. 2019

Preprint

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Background:Brain-derived neurotrophic factor (BDNF) is a major signaling molecule that the brain uses to control a vast network of intracellular cascades fundamental to properties of learning and memory, and cognition.While much is known about BDNF signaling in the healthy nervous system where it controls the mitogen activated protein kinase (MAPK) and cyclic-AMP pathways, less is known about its role in multiple brain disorders where it contributes to the dysregulated neuroplasticity seen in epilepsy and traumatic brain injury (TBI). We previously found that neurons respond to prolonged BDNF exposure (both in vivo (in models of epilepsy and TBI) and in vitro (in BDNF treated primary neuronal cultures)) by activating the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway. This pathway is best known for its association with inflammatory cytokines in non-neuronal cells. Results:Here, using deep RNA-sequencing of neurons exposed to BDNF in the presence and absence of well characterized JAK/STAT inhibitors, and without non-neuronal cells, we determine the BDNF transcriptome that is specifically reliant on JAK/STAT signaling. Surprisingly, the transcriptome contains ion channels and neurotransmitter receptors coming from all the major classes expressed in the brain, along with key modulators of synaptic plasticity, neurogenesis, and axonal remodeling. Analysis of this dataset has also provided a window on the unique mechanism of JAK/STATs in neurons as differential

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Section: Discussionmentioning

confidence: 99%

Section: Comparison Of Degs With Chip-seq Datasetsmentioning

confidence: 99%

Transcriptomic analysis of the BDNF-induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression

Cogswell

et al. 2019

Preprint

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“…To date, the only GRM1 mutations identified have been found to cause an autosomal recessive spinocerebellar ataxia (SCAR13; [229]). Recently, Watson and colleagues reported heterozygous dominant mutations in GRM1 gene that are associated with distinct disease phenotypes: gain-of-function point mutations that lead to enhanced receptor activity causing an adult-onset cerebellar ataxia and a truncation mutation that result in a dominant-negative effect causing a juvenile-onset cerebellar ataxia characterized by cognitive impairment (SCA44; Table 1) [230]. mGluR1 loss of function has been revealed in some animal models of human cerebellar ataxia, such as SCA1 and SCA3 transgenic mice.…”

Section: Mutations In the Gmr1 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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“…The complexity of InsP3R1-mediated calcium signaling is further illustrated by the identification of recessive truncating mutations and/or de novo mutations in ITPR1 underlying Gilespie syndrome characterized by congenital ataxia, intellectual disability and iris hypoplasia [45]. Recently, mutations were identified in GRM1 encoding the metabotrophic glutamate receptor mGluR1 that triggers IP3 production upon PF stimulation to cause SCA44 [46]. Functional impairment of mGluR1 signaling was also observed in mouse SCA3 PCs [47], and mGluR1 mutant mice showed pronounced motor deficits, ataxic features and were deficient in cerebellar LTD affecting motor learning [48].…”

Section: Phosphatidylinosytol Signaling System and Inositol Phosphatementioning

confidence: 99%

Why do so many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia?

Huang

Verbeek

2019

Neuroscience Letters

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The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia.

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Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

Cited by 67 publications

References 43 publications

Transcriptomic analysis of the BDNF-induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression

Transcriptomic analysis of the BDNF-induced JAK/STAT pathway in neurons: a window into epilepsy-associated gene expression

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

Why do so many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia?

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