Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I
Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I
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DOI：
10.1016/j.ajhg.2010.09.010
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发表时间：
2010-10-08
影响因子：
9.8
通讯作者：
Timmerman, Vincent
中科院分区：
文献类型：
--
作者：
Rotthier, Annelies;Auer-Grumbach, Michaela;Timmerman, Vincent
遗传性感觉和自主神经病变I型（HSAN-I）是与进行性远端感觉丧失和严重溃疡相关的轴突周围神经病变。酶丝氨酸棕榈酰转移酶（SPT）的第一亚基中的突变与HSAN-I相关。SPT酶催化从头鞘脂合成途径中的第一和限速步骤。不同的研究表明在HSAN-1的病理学中有其他基因的暗示。因此，我们在78名HSAN患者的队列中筛选了SPT的另外两个已知亚基SPTLC 2和SPTLC 3，在SPTLC 3中没有发现突变，但是我们在具有典型HSAN-1表型的四个家族的SPTLC 2亚基中鉴定了三个杂合错义突变。我们证明这些突变导致体外和体内SPT活性的部分至完全丧失。此外，它们引起非典型和神经毒性类鞘氨醇代谢物I-脱氧-二氢鞘氨醇的积累。我们的发现扩展了HSAN-I的遗传异质性，并扩大了与SPT缺陷相关的HSAN神经病的组。我们进一步表明，HSAN-I始终与神经毒性1-脱氧神经鞘氨醇的形成增加有关，这表明HSAN-I的共同病理机制。
Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway However, different studies suggest the implication of other genes in the pathology of HSAN-I Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of with four families presenting with a typical HSAN-I phenotype We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite I-deoxy-sphinganine Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an Increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.