Progressive sensory neuropathy in children

Johnson, Ralph H.; Spalding, J. M. K.

doi:10.1136/jnnp.27.2.125

Cited by 34 publications

(2 citation statements)

References 19 publications

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“…HSAN type 2 (HSANII, OMIM#201300) is of autosomal recessive inheritance and is characterized by an early onset sensory neuropathy, causing patients to lack all sensory modalities in a strictly peripheral glove-and-stocking distribution leading to a diagnosis in the first two decades of life 2. Other characteristics include a loss of tendon reflex, skin ulceration, Charcot joint, and spontaneous amputations while excluding motor involvement 3,4,5. In addition, upon sural nerve biopsy in affected patients, a reduction in the number of myelinated fibers is observed as well as a slight decrease in the number of non-myelinated fibers 6,7.…”

Section: Introductionmentioning

confidence: 99%

WNK1/HSN2 Mutation in Human Peripheral Neuropathy Deregulates KCC2 Expression and Posterior Lateral Line Development in Zebrafish (Danio rerio)

et al. 2013

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Hereditary sensory and autonomic neuropathy type 2 (HSNAII) is a rare pathology characterized by an early onset of severe sensory loss (all modalities) in the distal limbs. It is due to autosomal recessive mutations confined to exon “HSN2” of the WNK1 (with-no-lysine protein kinase 1) serine-threonine kinase. While this kinase is well studied in the kidneys, little is known about its role in the nervous system. We hypothesized that the truncating mutations present in the neural-specific HSN2 exon lead to a loss-of-function of the WNK1 kinase, impairing development of the peripheral sensory system. To investigate the mechanisms by which the loss of WNK1/HSN2 isoform function causes HSANII, we used the embryonic zebrafish model and observed strong expression of WNK1/HSN2 in neuromasts of the peripheral lateral line (PLL) system by immunohistochemistry. Knocking down wnk1/hsn2 in embryos using antisense morpholino oligonucleotides led to improper PLL development. We then investigated the reported interaction between the WNK1 kinase and neuronal potassium chloride cotransporter KCC2, as this transporter is a target of WNK1 phosphorylation. In situ hybridization revealed kcc2 expression in mature neuromasts of the PLL and semi-quantitative RT–PCR of wnk1/hsn2 knockdown embryos showed an increased expression of kcc2 mRNA. Furthermore, overexpression of human KCC2 mRNA in embryos replicated the wnk1/hsn2 knockdown phenotype. We validated these results by obtaining double knockdown embryos, both for wnk1/hsn2 and kcc2, which alleviated the PLL defects. Interestingly, overexpression of inactive mutant KCC2-C568A, which does not extrude ions, allowed a phenocopy of the PLL defects. These results suggest a pathway in which WNK1/HSN2 interacts with KCC2, producing a novel regulation of its transcription independent of KCC2's activation, where a loss-of-function mutation in WNK1 induces an overexpression of KCC2 and hinders proper peripheral sensory nerve development, a hallmark of HSANII.

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