Hereditary sensory and autonomic neuropathy Type 1 (HSAN1) is a rare autosomal dominantly inherited neuropathy, clinically characterized by a loss of distal peripheral sensory and motoneuronal function. Mutations in subunits of serine palmitoyltransferase (SPT) have been linked to the majority of HSAN1 cases. SPTs catalyze the condensation of l-serine with palmitoyl-CoA, the first committed and rate-limiting step in de novo sphingolipid biosynthesis. Despite extensive investigation, the molecular pathogenesis of HSAN1 remains controversial. Here, we established a Caenorhabditis elegans (C. elegans) model of HSAN1 by generating a sptl-1(c363g) mutation, encoding SPTL-1(C121W) and equivalent to human SPTLC1^C133W, at the C. elegans genomic locus through CRISPR. The sptl-1(c363g) homozygous mutants exhibited the same larval lethality and epithelial polarity defect as observed in sptl-1(RNAi) animals, suggesting a loss-of-function effect of the SPTL-1(C121W) mutation. sptl-1(c363g)/+ heterozygous mutants displayed sensory dysfunction with concomitant neuronal morphology and axon-dendrite polarity defects, demonstrating that the C. elegans model recapitulates characteristics of the human disease. sptl-1(c363g)-derived neuronal defects were copied in animals with defective sphingolipid biosynthetic enzymes downstream of SPTL-1, including ceramide glucosyltransferases, suggesting that SPTLC1^C133W contributes to the HSAN1 pathogenesis by limiting the production of complex sphingolipids, including glucosylceramide. Overexpression of SPTL-1(C121W) led to similar epithelial and neuronal defects and to reduced levels of complex sphingolipids, specifically glucosylceramide, consistent with a dominant-negative effect of SPTL-1(C121W) that is mediated by loss of this downstream product. Genetic interactions between SPTL-1(C121W) and components of directional trafficking in neurons suggest that the neuronal polarity phenotype could be caused by glycosphingolipid-dependent defects in polarized vesicular trafficking.SIGNIFICANCE STATEMENT The symptoms of inherited metabolic diseases are often attributed to the accumulation of toxic intermediates or byproducts, no matter whether the disease-causing enzyme participates in a biosynthetic or a degradation pathway. By showing that the phenotypes observed in a C. elegans model of HSAN1 disease could be caused by loss of a downstream product (glucosylceramide) rather than the accumulation of a toxic byproduct, our work provides new insights into the origins of the symptoms of inherited metabolic diseases while expanding the repertoire of sphingolipid functions, specifically, of glucosylceramides. These findings not only have their most immediate relevance for neuroprotective treatments for HSAN1, they may also have implications for a much broader range of neurologic conditions.

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