A role for KCC3 in maintaining cell volume of peripheral nerve fibers

Flores, Bianca; Schornak, Cara C.; Delpire, Eric

doi:10.1016/j.neuint.2018.01.009

Cited by 23 publications

(18 citation statements)

References 60 publications

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“…These evolutionarily conserved transporters 27 are of particular importance in regulation of ion and water homeostasis in mammalian central nervous system (CNS) 28,29 . The coordinated regulation of CCC function is important for cell volume regulation in most brain cells, preventing excessive cell swelling or shrinkage in response to osmotic or ischemic stress 26,[30][31][32][33][34] . The central importance of CCCs to choroid plexus regulation of CSF homeostasis has been recently recognized 1,3 .…”

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confidence: 99%

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

et al. 2020

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The SLC12A cation-Cl − cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano) methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.

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confidence: 99%

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

et al. 2020

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“…However, not significant, a slightly decreased sciatic nerve amplitude could be observed in the heterozygous mice compared with that of the wild-type mice 15. While the heterozygote mice do not display an overt phenotype, their nerve fibres showed intermediate shrinkage when compared with wild-type or homozygote mice 20…”

Section: Discussionmentioning

confidence: 77%

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

Park

Flores

Scherer³

et al. 2019

J Med Genet

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BackgroundCharcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.MethodsWe evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.ResultsWe identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.ConclusionOur findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

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“…Their structure, function and regulation are highly conserved across evolution, and despite their high homology, they exhibit unique patterns of distribution and fulfill distinct biophysical and physiological roles. [16][17] The functional properties of SLC12A6 are even more complex because it can exist in many isoforms that can be organized as homo-or hetero-oligomers with other cation-Clcotransporters. 18 The SLC12A6 cotransporter is broadly expressed throughout the brain, spinal cord and peripheral nervous system, amongst other various tissue locations.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore believed to have a key role in cell volume homeostasis and neuronal activity control. [16][17][18] Naturally occurring disease-causing variants in SLC12A6 are so far only described in humans, where they cause "agenesis of the corpus callosum with peripheral neuropathy"…”

Section: Discussionmentioning

confidence: 99%

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

et al. 2019

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Clinical, pathological and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole exome sequencing identified the SLC12A6 c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This lossof-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), due to a dysfunction of this K +-Clcotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis and myokymia-like muscle contractions have not been described in humans with ACCPN so far. Since this is the first report of a naturally occurring disease-causing SLC12A6 variant in a nonhuman species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.

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A role for KCC3 in maintaining cell volume of peripheral nerve fibers

Cited by 23 publications

References 60 publications

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

Modulation of brain cation-Cl− cotransport via the SPAK kinase inhibitor ZT-1a

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

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