Human Molecular Genetics Advance Access originally published online on October 6, 2005
Human Molecular Genetics 2005 14(22):3507-3521; doi:10.1093/hmg/ddi380
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Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy
1Day Laboratory for Neuromuscular Research, 2Alzheimer's Research Unit, Mass General Institute for Neurodegenerative Disease, 3Neural Plasticity Research Group, Department of Anesthesia and Critical Care, 4C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA, 5Department of Biochemistry and Molecular Biology, 6Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20184-4799, USA and 7Laboratory of Neurosciences, National Institute on Ageing Intramural Research Program, Baltimore, MD 21224, USA
* To whom correspondence should be addressed. Tel: +1 6177245334; Fax: +1 6177248543; Email: amccampbell{at}partners.org
Received August 5, 2005; Accepted October 3, 2005
Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause hereditary sensory and autonomic neuropathy (type I) (HSAN1), an adult onset, autosomal dominant neuropathy. HSAN1 patients have reduced SPT activity. Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity. We created transgenic mouse lines that ubiquitously overexpress either wild-type (SPTLC1WT) or mutant SPTLC1 (SPTLC1C133W). We report here that SPTLC1C133W mice develop age-dependent weight loss and mild sensory and motor impairments. Aged SPTLC1C133W mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning. There is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved. In the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased. These mice represent a novel mouse model of peripheral neuropathy and confirm the link between mutant SPT and neuronal dysfunction.
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