A Missense Variant in<i>KCNJ10</i>in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1)

Mauri, Nico; Kleiter, Miriam; Leschnik, Michael; Högler, Sandra; Dietschi, Elisabeth; Wiedmer, Michaela; Dietrich, Joëlle; Henke, Diana; Steffen, Frank; Schüller, Simone; Gurtner, Corinne; Stokar-Regenscheit, Nadine; O’Toole, Donal; Bilzer, Thomas; Herden, Christiane; Oevermann, Anna; Jagannathan, Vidhya; Leeb, Tosso

doi:10.1534/g3.116.038455

Cited by 23 publications

(59 citation statements)

References 27 publications

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“…We studied ataxias in the Belgian Shepherd breed and recently reported a candidate causative variant in the KCNJ10 gene for spongy degeneration with cerebellar ataxia, subtype 1 (SDCA1). This study revealed an unexpected genetic heterogeneity in clinically comparable cases, suggesting that more than one type of cerebellar ataxia is present in Belgian Shepherd dogs ( Kleiter et al 2011 ; Mauri et al 2017 ). The KCNJ10 variant was also identified in an independent study ( Stee et al 2016 ; Van Poucke et al 2017 ).…”

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A SINE Insertion inATP1B2in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)

Mauri

Kleiter

Dietschi

et al. 2017

G3 Genes|Genomes|Genetics

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Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ∼10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the ATP1B2 gene encoding the β2 subunit of the Na+/K+-ATPase holoenzyme (ATP1B2:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. Atp1b2 knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider ATP1B2:c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed. ATP1B2 thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder.

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confidence: 70%

“…We used the same animals as in our previous study ( Mauri et al 2017 ). We investigated six related Malinois families in which 12 puppies showed clinical signs of cerebellar dysfunction ( Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

A SINE Insertion inATP1B2in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)

Mauri

Kleiter

Dietschi

et al. 2017

G3 Genes|Genomes|Genetics

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“…Underscoring the importance of this channel for normal CNS functioning, individuals harboring homozygous mutations in Kcnj10 , the gene which encodes the Kir4.1 protein, present with several neurological symptoms including early onset tonic‐clonic seizures, ataxia, sensorineural deafness, and developmental delay (Bockenhauer et al, ; Reichold et al, ; Scholl et al, ). Intriguingly, several terrier dog breeds with homozygous mutations in Kir4.1 present with seizures and cerebellar ataxia (Gilliam et al, ; Rohdin et al, ) and cerebellar ataxia and spongy degeneration were also reported in Belgian shepherds with homozygous missense mutations in Kir4.1 (Mauri et al, ). Kir4.1 was identified as a seizure susceptibility gene in both mice and humans (Buono et al, ; Lenzen et al, ).…”

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confidence: 99%

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Boni

Kahanovitch

Nwaobi

et al. 2020

Glia

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Kir4.1, a glial-specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K + homeostasis. Underscoring the role of Kir4.1 in central nervous system (CNS) functioning, genetic mutations in KCNJ10, the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans.Kir4.1 protein and mRNA loss are consistently observed in CNS injury and neurological diseases linked to hyperexcitability and neuronal dysfunction, leading to the notion that Kir4.1 represents an attractive therapeutic target. Despite this, little is understood regarding the mechanisms that underpin this downregulation. Previous work by our lab revealed that DNA hypomethylation of the Kcnj10 gene functions to regulate mRNA levels during astrocyte maturation whereas hypermethylation in vitro led to decreased promoter activity. In the present study, we utilized two vastly different injury models with known acute and chronic loss of Kir4.1 protein and mRNA to evaluate the methylation status of Kcnj10 as a candidate molecular mechanism for reduced transcription and subsequent protein loss. Examining whole hippocampal tissue and isolated astrocytes, in a lithium-pilocarpine model of epilepsy, we consistently identified hypermethylation of CpG island two, which resides in the large intronic region spanning the Kcnj10 gene. Strikingly similar results were observed using the second injury paradigm, a fifth cervical (C5) vertebral hemi-contusion model of spinal cord injury. Our previous work indicates the same gene region is significantly hypomethylated when transcription increases during astrocyte maturation.Our results suggest that DNA methylation can bidirectionally modulate Kcnj10 transcription and may represent a targetable molecular mechanism for the restoring astroglial Kir4.1 expression following CNS insult. K E Y W O R D S astrocyte, DNA methylation, Kcnj10, Kir4.1, Pilocarpine

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“…Multiple examples of hereditary ataxia have been described in purebred dogs [3][4][5][6][7][8][9]. Although the specific diseases are often rare, and the genetic mutations can be breed-specific, hereditary ataxia is a key cause of movement disorders in dogs.…”

Section: Introductionmentioning

confidence: 99%

“…Although the specific diseases are often rare, and the genetic mutations can be breed-specific, hereditary ataxia is a key cause of movement disorders in dogs. Canine hereditary ataxia is typically inherited in an autosomal recessive manner, and disease-causing variants have been identified for some breeds [3][4][5][6][7][8][9][10][11][12]. Some of the genes implicated in canine ataxia had not previously been associated with disease in humans [12][13][14][15], whereas other forms of canine ataxia are caused by variants within the same genes that are associated with well characterised forms of human ataxia [4][5][6]16].…”

Section: Introductionmentioning

confidence: 99%

Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs

et al. 2020

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A form of hereditary cerebellar ataxia has recently been described in the Norwegian Buhund dog breed. This study aimed to identify the genetic cause of the disease. Whole-genome sequencing of two Norwegian Buhund siblings diagnosed with progressive cerebellar ataxia was carried out, and sequences compared with 405 whole genome sequences of dogs of other breeds to filter benign common variants. Nine variants predicted to be deleterious segregated among the genomes in concordance with an autosomal recessive mode of inheritance, only one of which segregated within the breed when genotyped in additional Norwegian Buhunds. In total this variant was assessed in 802 whole genome sequences, and genotyped in an additional 505 unaffected dogs (including 146 Buhunds), and only four affected Norwegian Buhunds were homozygous for the variant. The variant identified, a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), is predicted to cause a tryptophan to arginine substitution in a highly conserved region of the potassium voltage-gated channel interacting protein KCNIP4. This gene has not been implicated previously in hereditary ataxia in any species. Evaluation of KCNIP4 protein expression through western blot and immunohistochemical analysis using cerebellum tissue of affected and control dogs demonstrated that the mutation causes a dramatic reduction of KCNIP4 protein expression. The expression of alternative KCNIP4 transcripts within the canine cerebellum, and regional differences in KCNIP4 protein expression, were characterised through RT-PCR and immunohistochemistry respectively. The voltage-gated potassium channel protein KCND3 has previously been implicated in spinocerebellar ataxia, and our findings suggest that the Kv4 channel complex KCNIP accessory subunits also have an essential role in PLOS Genetics | https://doi.

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A Missense Variant inKCNJ10in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA1)

Cited by 23 publications

References 27 publications

A SINE Insertion inATP1B2in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)

A SINE Insertion inATP1B2in Belgian Shepherd Dogs Affected by Spongy Degeneration with Cerebellar Ataxia (SDCA2)

DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult

Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs

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