Novel Homozygous KCNJ10 Mutation in a Patient with Non-syndromic Early-Onset Cerebellar Ataxia

Nicita, Francesco; Tasca, Giorgio; Nardella, Marta; Bellacchio, Emanuele; Camponeschi, Ilaria; Vasco, Gessica; Schirinzi, Tommaso; Bertini, Enrico; Zanni, Ginevra

doi:10.1007/s12311-018-0924-7

Cited by 10 publications

(6 citation statements)

References 15 publications

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“…We validated previously reported decrease in the expression of glutamate transporter Slc1a3 in Bergmann glia [70], and identified additional perturbations in the expression of homeostatic genes such as Kcnj10 that are critical for PC function [97][57]. Moreover, our results suggest perturbed Shh signaling as one possible mechanism of these BG molecular alterations.…”

Section: Discussionsupporting

confidence: 86%

Single-nuclei RNA sequencing uncovers non-cell autonomous changes in cerebellar astrocytes and oligodendrocytes that may contribute to Spinocerebellar Ataxia Type 1 (SCA1) pathogenesis

Borgenheimer

Zhang

Cvetanović

2021

Preprint

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Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1). While mutant ATXN1 is expressed throughout the brain, SCA1 is characterized by severe degeneration of cerebellar Purkinje cells (PCs) and cerebellar gliosis. It is likely that cerebellar microenvironment and in particular glial cells contribute to the Purkinje cell specific vulnerability in SCA1. We have used single nuclei RNA sequencing (snRNA seq) to uncover effects of mutant ATXN1 on PCs gene expression changes as well as non-cell autonomous changes in glial cells transcriptomes in cerebella of Pcp2-ATXN1[82Q] mice, a transgenic SCA1 mouse model expressing mutant ATXN1 only in PCs cells

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Section: Discussionsupporting

confidence: 86%

Single-nuclei RNA sequencing uncovers non-cell autonomous changes in cerebellar astrocytes and oligodendrocytes that may contribute to Spinocerebellar Ataxia Type 1 (SCA1) pathogenesis

Borgenheimer

Zhang

Cvetanović

2021

Preprint

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“…Some of the transcriptional changes found in both studies occur in genes encoding potassium channels (Kcnc1, Kcnj10), voltage gated calcium channels (Cacna1b, Cacna1e), and membrane transporters (Slc38a1, Slc39a9) that all have the potential to change the intrinsic excitability of cerebellar Purkinje and nuclei cells. Furthermore, these studies found changes in transcription of genes that are associated with dystonia (Cacna1b, Cacna1e) and ataxia (Car8, Grid2, Grik2, Kcnc1, Kcnj10) (Kaya et al 2011;Utine et al 2013;Groen et al 2015;Guzmán et al 2017;Nicita et al 2018;Helbig et al 2018;. Since these molecular analyses were performed using bulk cerebellar tissue and because Thap1 is universally expressed in the cerebellar circuit, including Purkinje cells, cerebellar nuclei cells and interneurons in the cerebellar cortex, the observed molecular changes could drive changes in the intrinsic excitability and firing patterns of all cerebellar neurons.…”

Section: Discussionmentioning

confidence: 99%

Abnormal cerebellar function and tremor in a mouse model for non‐manifesting partially penetrant dystonia type 6

Heijden

Kizek

Perez

et al. 2021

The Journal of Physiology

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Loss-of-function mutations in the Thap1 gene cause partially penetrant dystonia type 6 (DYT6). r Some non-manifesting DYT6 mutation carriers have tremor and abnormal cerebellothalamo-cortical signalling. r We show that Thap1 heterozygote mice have action tremor, a reduction in cerebellar neuron number, and abnormal electrophysiological signals in the remaining neurons. r These results underscore the importance of Thap1 levels for cerebellar function. r These results uncover how cerebellar abnormalities contribute to different dystonia-associated motor symptoms.

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“…This could explain the lack of neurological symptoms, as only the kidney shows a complete co-localization of these two subunits. Conversely, no kidney involvement has been found in two patients with a Kir4.1 mutation affecting isoleucine 60 (I60T and I60M; Al Dhaibani et al, 2018 ; Nicita et al, 2018 ), suggesting that in this case, coexpression with Kir5.1 rescues the functional defect. These unusual mutations are colored in pink.…”

Section: East/sesame Syndrome: a Pleiotropic Monogenetic Disease Caus...mentioning

confidence: 82%

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

Forst

Warth

et al. 2022

Front. Physiol.

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In 2009, two groups independently linked human mutations in the inwardly rectifying K+ channel Kir4.1 (gene name KCNJ10) to a syndrome affecting the central nervous system (CNS), hearing, and renal tubular salt reabsorption. The autosomal recessive syndrome has been named EAST (epilepsy, ataxia, sensorineural deafness, and renal tubulopathy) or SeSAME syndrome (seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance), accordingly. Renal dysfunction in EAST/SeSAME patients results in loss of Na+, K+, and Mg2+ with urine, activation of the renin–angiotensin–aldosterone system, and hypokalemic metabolic alkalosis. Kir4.1 is highly expressed in affected organs: the CNS, inner ear, and kidney. In the kidney, it mostly forms heteromeric channels with Kir5.1 (KCNJ16). Biallelic loss-of-function mutations of Kir5.1 can also have disease significance, but the clinical symptoms differ substantially from those of EAST/SeSAME syndrome: although sensorineural hearing loss and hypokalemia are replicated, there is no alkalosis, but rather acidosis of variable severity; in contrast to EAST/SeSAME syndrome, the CNS is unaffected. This review provides a framework for understanding some of these differences and will guide the reader through the growing literature on Kir4.1 and Kir5.1, discussing the complex disease mechanisms and the variable expression of disease symptoms from a molecular and systems physiology perspective. Knowledge of the pathophysiology of these diseases and their multifaceted clinical spectrum is an important prerequisite for making the correct diagnosis and forms the basis for personalized therapies.

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Novel Homozygous KCNJ10 Mutation in a Patient with Non-syndromic Early-Onset Cerebellar Ataxia

Cited by 10 publications

References 15 publications

Single-nuclei RNA sequencing uncovers non-cell autonomous changes in cerebellar astrocytes and oligodendrocytes that may contribute to Spinocerebellar Ataxia Type 1 (SCA1) pathogenesis

Single-nuclei RNA sequencing uncovers non-cell autonomous changes in cerebellar astrocytes and oligodendrocytes that may contribute to Spinocerebellar Ataxia Type 1 (SCA1) pathogenesis

Abnormal cerebellar function and tremor in a mouse model for non‐manifesting partially penetrant dystonia type 6

EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies

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