HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship
HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship
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DOI：
10.1093/hmg/ddv611
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发表时间：
2016-03-01
影响因子：
3.5
通讯作者：
Hornemann, Thorsten
中科院分区：
文献类型：
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作者：
Bode, Heiko;Bourquin, Florence;Hornemann, Thorsten
遗传性感觉和自主神经病变1型（HSAN 1）是一种罕见的常染色体显性遗传性周围神经病变，由丝氨酸棕榈酰转移酶（SPT）的SPTLC 1和SPTLC 2亚基突变引起。这些突变诱导底物偏好从L-丝氨酸永久转变为L-丙氨酸，导致非典型和神经毒性1-脱氧鞘脂（1-deoxySL）的病理形成。在这里，我们比较了11个SPTLC 1和6个SPTLC 2突变体的酶的性质，使用统一的同位素标记的方法。总共有8种SPT突变体（STPLC 1 p.C133W、p.C133Y、p.S331F、p.S331Y和SPTLC 2 p.A182P、p.G382V、p.S384F、p.I504F）与1-脱氧SL合成增加相关。尽管早期的报道，典型的活动与L-丝氨酸没有减少在任何调查的SPT突变体。三种变体（SPTLC1p.S331F/Y和SPTLC2p.I505Y）显示出增加的典型活性和增加的C-20鞘氨醇碱形成。这三种突变与异常严重的HSAN 1表型相关，并且在患者血浆中也证实了C-20鞘氨醇水平升高。分析的鞘氨醇类碱基的主成分分析将突变聚类为三个独立的实体。每个聚类与不同的临床结果（无、轻度和重度HSAN 1表型）相关。基于原核SPT的蛋白质结构的同源性模型在结构水平上概括了相同的分组。与轻度形式相关的突变聚集在活性位点周围，而与严重形式相关的突变位于蛋白质表面。总之，我们发现SPT中的HSAN 1突变具有独特的生化特性，这允许基于血浆鞘氨醇碱基谱预测临床症状。
Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare autosomal dominant inherited peripheral neuropathy caused by mutations in the SPTLC1 and SPTLC2 subunits of serine palmitoyltransferase (SPT). The mutations induce a permanent shift in the substrate preference from L-serine to L-alanine, which results in the pathological formation of atypical and neurotoxic 1-deoxy-sphingolipids (1-deoxySL). Here we compared the enzymatic properties of 11 SPTLC1 and six SPTLC2 mutants using a uniform isotope labelling approach. In total, eight SPT mutants (STPLC1p.C133W, p.C133Y, p.S331F, p.S331Y and SPTLC2p.A182P, p.G382V, p.S384F, p.I504F) were associated with increased 1-deoxySL synthesis. Despite earlier reports, canonical activity with L-serine was not reduced in any of the investigated SPT mutants. Three variants (SPTLC1p.S331F/Y and SPTLC2p.I505Y) showed an increased canonical activity and increased formation of C-20 sphingoid bases. These three mutations are associated with an exceptionally severe HSAN1 phenotype, and increased C-20 sphingosine levels were also confirmed in plasma of patients. A principal component analysis of the analysed sphingoid bases clustered the mutations into three separate entities. Each cluster was related to a distinct clinical outcome (no, mild and severe HSAN1 phenotype). A homology model based on the protein structure of the prokaryotic SPT recapitulated the same grouping on a structural level. Mutations associated with the mild form clustered around the active site, whereas mutations associated with the severe form were located on the surface of the protein. In conclusion, we showed that HSAN1 mutations in SPT have distinct biochemical properties, which allowed for the prediction of the clinical symptoms on the basis of the plasma sphingoid base profile.