age-dependent neuropathy: Mutant SPTLC1 dominantly inhibits serine palmitoyltran

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Hum Mol Genet. 2005 Oct 6

Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase

activity in vivo and confers an age-dependent neuropathy.

Mc A, Truong D, Broom DC, Allchorne A, Gable K, Cutler RG,

Mattson MP, Woolf CJ, Frosch MP, Harmon JM, Dunn TM, Brown RH Jr.

Day Laboratory for Neuromuscular Research, Massachusetts General

Hospital and Harvard Medical School, town, MA 02129, USA.

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 (SPTLC1

(WT)) or mutant SPTLC1 (SPTLC1(C133W)). We report here that SPTLC1

(C133W) mice develop age-dependent weight loss and mild sensory and

motor impairments. Aged SPTLC1(C133W) 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.