Abstract
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.
Highlights
Hereditary sensory and autonomic neuropathies (HSAN) are rare inherited neuropathies predominantly characterized by sensory dysfunction associated with variable degrees of autonomous and motor involvement
Hereditary sensory and autonomic neuropathy type 2 (HSANII) is a rare human pathology characterized by the early loss of sensory perception
It arises from expression of autosomal recessive mutations confined to an alternatively spliced exon of the WNK1 serine-threonine kinase, which confers nervous system specificity
Summary
Hereditary sensory and autonomic neuropathies (HSAN) are rare inherited neuropathies predominantly characterized by sensory dysfunction associated with variable degrees of autonomous and motor involvement. HSANs were first classified in five distinct types according to clinical presentation of symptoms as well as age of onset and mode of inheritance [1]. These distinct categories were later confirmed by identification of causative mutations by genome linkage studies, revealing heterogeneity amongst HSAN types both clinically and genetically. 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]. Despite there being published cases of HSANII since the last century, the mechanism leading to this disorder is still not understood
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