Characterization of Two Mutations in the SPTLC1 Subunit of Serine Palmitoyltransferase Associated with Hereditary Sensory and Autonomic Neuropathy Type I
Characterization of Two Mutations in the SPTLC1 Subunit of Serine Palmitoyltransferase Associated with Hereditary Sensory and Autonomic Neuropathy Type I
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DOI：
10.1002/humu.21481
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发表时间：
2011-06-01
期刊：
影响因子：
3.9
通讯作者：
Janssens, Katrien
中科院分区：
文献类型：
--
作者：
Rotthier, Annelies;Penno, Anke;Janssens, Katrien
遗传性感觉和自主神经病变I型（HSAN-I）是一种轴突周围神经病变，导致进行性远端感觉丧失和严重溃疡。据报道，编码丝氨酸棕榈酰转移酶（SPT）的两个亚基的SPTLC 1和SPTLC 2突变可引起HSAN-I，SPT是催化鞘脂从头合成的第一步和限速步骤的酶。在这里，我们证明了SPTLC 1突变p.S331F和p.A352V导致体外SPT活性降低，并与患者血浆样品中脱氧鞘氨醇碱1-脱氧-鞘氨醇和1-脱氧甲基-鞘氨醇水平增加有关。稳定表达p. S331 F-SPTLC 1的HEK 293 T细胞系同样显示脱氧鞘氨醇类碱基的积累，但在过表达p. A352 V-SPTLC 1的HEK 293 T细胞中未观察到这种积累。这些结果证实，脱氧鞘氨醇类碱基的形成增加是HSAN-I的一个关键特征，因为它与迄今为止报道的所有致病性SPTLC 1和SPTLC 2突变相关，但也需要谨慎解释体外数据。(C)2011 Wiley-Liss，Inc.
Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy leading to progressive distal sensory loss and severe ulcerations. Mutations in SPTLC1 and SPTLC2, encoding the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids, have been reported to cause HSAN-I. Here, we demonstrate that the SPTLC1 mutations p.S331F and p. A352V result in a reduction of SPT activity in vitro and are associated with increased levels of the deoxysphingoid bases 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine in patients' plasma samples. Stably expressing p.S331F-SPTLC1 HEK293T cell lines likewise show accumulation of deoxysphingoid bases, but this accumulation is not observed in HEK293T cells overexpressing p.A352V-SPTLC1. These results confirm that the increased formation of deoxysphingoid bases is a key feature for HSAN-I as it is associated with all pathogenic SPTLC1 and SPTLC2 mutations reported so far, but also warrant for caution in the interpretation of in vitro data. (C) 2011 Wiley-Liss, Inc.