A knockin mouse allele of Sptlc1-C133W, a model of hereditary autonomic and sensory neuropathy type 1 (HSAN1).


What’s New in ALS and CMT - molecular pathways, mutations, phenotype-genotype correlations

Poster Number: 210


Courtney Hatton, Abigail Tadenev, Thorsten Hornemann, Robert Burgess, PhD


1. The Jackson Laboratory, 2. The Jackson Laboratory, 3. University of Zurich, Institute for Clinical Chemistry, 4. The Jackson Laboratory

Hereditary autonomic and sensory neuropathy (HSAN1) is caused by dominant mutations in serine palmitoyltransferase long chain 1 or 2 (SPTLC1/2), components of an enzyme complex that charges serine onto palmitoylate as a first step in sphingolipid biosynthesis. Mutations in SPTLC1 alter the enzyme’s substrate specificity, allowing amino acids other than serine to be added and creating unnatural deoxysphingoid base intermediates (DSBs) that are toxic to neurons. Transgenic mouse models expressing the C133W allele of SPTLC1 have been reported, and these mice recapitulate many aspects of the human disease. In addition, homozygous null (knockout) mice are lethal, and heterozygous nulls do not have a phenotype. Here we report a knockin mouse allele of Sptlc1C133W to produce an animal model for preclinical studies that avoids possible complications of a transgenic model, such as overexpression or misexpression of the mutant protein. Interestingly, these mice do not survive as homozygotes, indicating that not only is the substrate specificity of SPTLC1 altered, but also that the normal, essential function of SPTLC1 is reduced or lost. These mice do develop elevated levels of DSB intermediates in several organs and in plasma by three-months-of-age. We are currently examining these mice in a variety of behavioral, neurophysiological, and histological experiments to determine if they also develop the anticipated sensory deficits and neuropathy. We are also treating these mice with elevated serine in an attempt to drive the correct enzymatic reaction, as reported for other models and in human trials. The full characterization of these mice will provide an additional model for preclinical studies in HSAN1.