Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis

摘要: Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited degenerative disorder of the peripheral nerves. HSN1 clinically and genetically heterogeneous. One form arises from mutations in gene SPTLC1 encoding long-chain base (LCB1), one two subunits serine palmitoyltransferase (SPT), enzyme catalyzing initial step sphingolipid synthesis. We have examined effects C133Y C133W, which we identified families, on function SPT. Although lymphoblasts, C133W do not alter steady-state levels LCB1 LCB2 subunits, they result reduced SPT activity Moreover, mutant Chinese hamster ovary (CHO) cell strain with defective due to lack subunit, these impair ability subunit complement deficiency. Furthermore, overproduction either LCB1C133Y or LCB1C133W inhibits CHO cells despite presence wild-type LCB1. In addition, demonstrate that proteins, similar normal LCB1, can interact subunit. These results indicate HSN1-associated confer dominant negative enzyme.