Human Molecular Genetics Advance Access published online on October 6, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi380
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1 Day Laboratory for Neuromuscular Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
* To whom correspondence should be addressed. 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 over-express 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, while 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.
Received August 5, 2005
Revised October 3, 2005
Accepted October 3, 2005
Article
Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy
2 Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
3 Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20184-4799, USA
4 Laboratory of Neurosciences, National Institute on Ageing Intramural Research Program, Baltimore, MD 21224
5 Alzheimer's Research Unit, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA; C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
6 Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20184-4799, USA
Alexander McCampbell, E-mail: amccampbell{at}partners.org
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