geneexpressionHSAN1 has been found to be associated with mutations in the genes, SPTLC1 and SPTLC2.  These genes encode two subunits of the protein, serine palmitoyltransferase (SPT), which is an enzyme responsible for regulating the production of sphingolipids.  More specifically, SPT catalyzes the first and rate-limiting ste p in de novo sphingolipid biosynthesis.  Sphingolipids play an important role in cell structure and signaling, namely in neuronal functioning, as evidenced by the fact that many neurodegenerative disorders are now known to be caused by mutations in the enzymes involved in sphingolipid metabolism.

It was previously hypothesized that mutations associated with HSAN1 brought about the neuropathy by causing either a reduction in SPT activity or creating an inherently toxic protein, similar to other neurodegenerative disorders.  However, it is now postulated, based on findings in both humans and mice, that HSAN1 is caused by the accumulation of two atypical deoxysphingoid bases (DSBs) created by an alteration in SPT substrate selectivity.  Since these DSBs cannot be further converted into complex sphingolipids or degraded, they accumulate in the cell as intermediate sphingolipid metabolites where they have been shown to have pronounced neurotoxic effects.

Simplified PowerPoint About HSAN1 (by Tami Newcomer Murphy)