Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis
Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis
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DOI：
10.1172/jci200216450
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发表时间：
2002-11-01
影响因子：
15.9
通讯作者：
Hanada, K
中科院分区：
文献类型：
--
作者：
Bejaoui, K;Uchida, Y;Hanada, K
遗传性感觉神经病1型（HSN 1）是一种显性遗传性周围神经退行性疾病。HSN1在临床和遗传上是异质性的。一种形式是由编码长链碱基1（LCB 1）的基因SPTLC 1突变引起的，LCB 1是丝氨酸棕榈酰转移酶（SPT）的两个亚基之一，SPT催化鞘脂合成的初始步骤。我们已经研究了突变C133Y和C133W的影响，我们已经确定在两个HSN 1家族，对SPT的功能。虽然在HSN 1淋巴母细胞中，C133Y和C133W突变不会改变LCB 1和LCB 2亚基的稳态水平，但它们会导致SPT活性和鞘脂合成降低。此外，在突变的中国仓鼠卵巢（CHO）细胞株由于缺乏LCB 1亚基而具有缺陷的SPT活性，这些突变损害了LCB 1亚基补充SPT缺陷的能力。此外，尽管存在野生型LCB 1，但过量产生LCB 1C133 Y或LCB 1C133 W亚基抑制CHO细胞中的SPT活性。此外，我们证明，在CHO细胞中的突变LCB 1蛋白，类似于正常的LCB 1，可以与野生型LCB 2亚基相互作用。这些结果表明，LCB 1中的HSN 1相关突变对SPT酶产生显性负效应。
Hereditary sensory neuropathy type 1 (HSN1) is a dominantly inherited degenerative disorder of the peripheral nerves. HSN1 is clinically and genetically heterogeneous. One form arises from mutations in the gene SPTLC1 encoding long-chain base 1 (LCB1), one of two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step of sphingolipid synthesis. We have examined the effects of the mutations C133Y and C133W, which we have identified in two HSN1 families, on the function of SPT. Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT activity and sphingolipid synthesis. Moreover, in a mutant Chinese hamster ovary (CHO) cell strain with defective SPT activity due to a lack of the LCB1 subunit, these mutations impair the ability of the LCB1 subunit to complement the SPT deficiency. Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W subunit inhibits SPT activity in CHO cells despite the presence of wild-type LCB1. In addition, we demonstrate that in CHO cells the mutant LCB1 proteins, similar to the normal LCB1, can interact with the wild-type LCB2 subunit. These results indicate that the HSN1-associated mutations in LCB1 confer dominant negative effects on the SPT enzyme.