WNK1 – Hereditary sensory and autonomic neuropathy type 2

Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is an early-onset autosomal recessive disorder characterized by severe loss of pain, temperature, and touch sensation due to degeneration of peripheral sensory neurons. The nervous system-specific HSN2 exon of WNK1 defines a distinct isoform (WNK1/HSN2) expressed predominantly in sensory neurons (PMID:18521183).

Genetic evidence for a gene–disease association is strong. A founder effect in Quebec underlies two truncating alleles (c.918_919insA (p.Gly307fs) and c.3276dup (p.Ser1093fs)) in 16 affected individuals across 13 families, all showing autosomal recessive inheritance (PMID:15911806). Additional homozygous frameshift and nonsense mutations have been reported in Japanese (c.1137dup (p.Ala380fs)), East European (c.2636G>A (p.Trp879Ter)), Chinese (c.2689> T (p.Glu897Ter)), and Pakistani families (c.3002T>G (p.Leu1001Ter)), with segregation of variants in affected pedigrees (PMID:16636245; PMID:22910560; PMID:39710744; PMID:31132985). All reported variants are predicted loss-of-function, consistent with a null mechanism.

Functional studies support a loss-of-function mechanism. Immunodetection in mouse shows Wnk1/hsn2 expression in peripheral sensory neurons and Schwann cells, mirroring human peripheral nerve distribution (PMID:18521183). Zebrafish wnk1/hsn2 knockdown yields defective peripheral lateral line development and upregulation of the KCC2 cotransporter; overexpression of active KCC2 phenocopies the sensory defect, indicating that WNK1/HSN2 regulates neuronal chloride homeostasis via KCC2 phosphorylation (PMID:25003007).

No conflicting or disputing genetic or functional evidence has been reported. The concordance of truncating variants in unrelated populations, clear segregation, and biologically relevant in vivo and in vitro assays underpin a definitive gene–disease relationship.

Key take-home: Truncating mutations in the nervous system-specific HSN2 exon of WNK1 cause autosomal recessive HSAN2 via loss of kinase function and dysregulation of neuronal chloride transport, informing molecular diagnosis and potential therapeutic targeting of KCC2 signaling.

References

• Neurology • 2005 • Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians. PMID:15911806
• Neurology • 2006 • New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2. PMID:16636245
• Acta biochimica Polonica • 2012 • A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2. PMID:22910560
• Journal of human genetics • 2025 • A novel mutation in the WNK1/HSN2 gene causing hereditary sensory and autonomic neuropathy type 2 in Chinese patient. PMID:39710744
• The Journal of clinical investigation • 2008 • Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. PMID:18521183
• Rare diseases (Austin, Tex.) • 2013 • WNK1/HSN2 isoform and the regulation of KCC2 activity. PMID:25003007
• BMC medical genetics • 2019 • The coexistence of a novel WNK1 variant and a copy number variation causes hereditary sensory and autonomic neuropathy type IIA. PMID:31132985

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