A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated
A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated
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DOI：
10.1007/s10048-008-0168-7
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发表时间：
2009-04-01
期刊：
影响因子：
2.2
通讯作者：
von Eckardstein, Arnold
中科院分区：
文献类型：
--
作者：
Hornemann, Thorsten;Penno, Anke;von Eckardstein, Arnold
遗传性感觉神经病1型（HSAN I）是一种常染色体显性遗传的周围神经系统神经退行性疾病，与丝氨酸棕榈酰转移酶（SPT）的SPTLC 1亚基突变相关。据报道，SPTLC 1的4个错义突变（C133 W、C133 Y、V144 D和G387 A）导致HSAN I。SPT催化丝氨酸和棕榈酰辅酶A的缩合，这是神经酰胺从头合成的第一步和限速步骤。早期的研究表明，C133 W和C133 Y突变体的活性降低，而V144 D和G387 A突变对人类酶的影响尚未测试。在本文中，我们表明，没有一个HSAN I突变干扰SPT复合物的形成。我们证明，V144 D也具有降低的SPT活性，但是降低的程度低于C133 W和C133 Y。相反，G387 A突变对SPT活性没有影响。此外，LY-B细胞（SPTLC 1缺陷CHO细胞系）的生长表型可以通过表达野生型SPTLC 1或G387 A突变体而逆转，但不能通过表达C133 W突变体逆转。这表明G387 A突变很可能与HSAN I没有直接关联。这些发现在遗传学上通过鉴定核HSAN家族得到证实，该家族显示G387 A变体作为非同义SNP的分离。
Hereditary sensory neuropathy type 1 (HSAN I) is an autosomal dominant inherited neurodegenerative disorder of the peripheral nervous system associated with mutations in the SPTLC1 subunit of the serine palmitoyltransferase (SPT). Four missense mutations (C133W, C133Y, V144D and G387A) in SPTLC1 were reported to cause HSAN I. SPT catalyses the condensation of Serine and Palmitoyl-CoA, which is the first and rate-limiting step in the de novo synthesis of ceramides. Earlier studies showed that C133W and C133Y mutants have a reduced activity, whereas the impact of the V144D and G387A mutations on the human enzyme was not tested yet. In this paper, we show that none of the HSAN I mutations interferes with SPT complex formation. We demonstrate that also V144D has a reduced SPT activity, however to a lower extent than C133W and C133Y. In contrast, the G387A mutation showed no influence on SPT activity. Furthermore, the growth phenotype of LY-B cells-a SPTLC1 deficient CHO cell line-could be reversed by expressing either the wild-type SPTLC1 or the G387A mutant, but not the C133W mutant. This indicates that the G387A mutation is most likely not directly associated with HSAN I. These findings were genetically confirmed by the identification of a nuclear HSAN family which showed segregation of the G387A variant as a non-synonymous SNP.