Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I

Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway However, different studies suggest the implication of other genes in the pathology of HSAN-I Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of with four families presenting with a typical HSAN-I phenotype We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite I-deoxy-sphinganine Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an Increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.