Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 (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, 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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PMID:Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy. 1621 Mar 80

The role of serine palmitoyltransferase (SPT) and de novo ceramide biosynthesis in cardiac ceramide and sphingomyelin metabolism is unclear. To determine whether the de novo synthetic pathways, rather than ceramide uptake from circulating lipoproteins, is important for heart ceramide levels, we created cardiomyocyte-specific deficiency of Sptlc2, a subunit of SPT. Heart-specific Sptlc2-deficient (hSptlc2 KO) mice had a >35% reduction in ceramide, which was limited to C18:0 and very long chain ceramides. Sphingomyelinase expression, and levels of sphingomyelin and diacylglycerol were unchanged. But surprisingly phospholipids and acyl CoAs contained increased saturated long chain fatty acids. hSptlc2 KO mice had decreased fractional shortening and thinning of the cardiac wall. While the genes regulating glucose and fatty acid metabolism were not changed, expression of cardiac failure markers and the genes involved in the formation of extracellular matrices were up-regulated in hSptlc2 KO hearts. In addition, ER-stress markers were up-regulated leading to increased apoptosis. These results suggest that Sptlc2-mediated de novo ceramide synthesis is an essential source of C18:0 and very long chain, but not of shorter chain, ceramides in the heart. Changes in heart lipids other than ceramide levels lead to cardiac toxicity.
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PMID:Cardiomyocyte specific deficiency of serine palmitoyltransferase subunit 2 reduces ceramide but leads to cardiac dysfunction. 2249 6