A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy
A missense mutation in the 3-ketodihydrosphingosine reductase FVT1 as candidate causal mutation for bovine spinal muscular atrophy
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DOI：
10.1073/pnas.0607721104
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发表时间：
2007-04-17
影响因子：
11.1
通讯作者：
Foerster, Martin
中科院分区：
文献类型：
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作者：
Krebs, Stefan;Medugorac, Ivica;Foerster, Martin
常染色体隐性遗传性神经退行性疾病脊髓性肌萎缩症（SMA）的牛形式显示出与人类形式的疾病惊人的相似性。然而，它已经被定位到不含有SMN基因的牛直向同源物的基因组区域，该基因的突变引起人SMA。在对定位结果进行细化后，我们分析了位置和功能候选基因。三个候选基因之一，FVT 1，编码3-酮二氢鞘氨醇还原酶，催化鞘糖脂代谢中的关键步骤，显示出G-至-A错义突变，将Ala-175变为Thr。所鉴定的突变仅限于受SMA影响的动物和携带者，并且总是出现在创始人单倍型的背景下。在健康动物中发现的Ala变体在体外酶测定中显示出预期的3-酮二氢鞘氨醇还原酶活性。重要的是，在SMA动物中发现的Thr变体没有显示出可检测的活性。令人惊讶的是，在体内测定中，突变基因补充同源酵母敲除菌株以及健康变体的生长缺陷。这一发现解释了受影响的新生小牛的生存能力和后来的神经元特异性疾病发作，这可能是由于这些神经元对管家功能变化的高度敏感性。综上所述，所述FVT 1突变是牛SMA因果关系的强有力候选因素。这一结果为理解SMA发展的潜在机制提供了动物模型，并将允许对牛的疾病进行有效的选择。
The bovine form of the autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) shows striking similarity to the human form of the disease. it has, however, been mapped to a genomic region not harboring the bovine orthologue of the SMN gene, mutation of which causes human SMA. After refinement of the mapping results we analyzed positional and functional candidate genes. One of three candidate genes, FVT1, encoding 3-ketodihydrosphingosine reductase, which catalyzes a crucial step in the glycosphingolipid metabolism, showed a G-to-A missense mutation that changes Ala-175 to Thr. The identified mutation is limited to SMA-affected animals and carriers and always appears in context of the founder haplotype. The Ala variant found in healthy animals showed the expected 3-ketoclihydrosphingosine reductase activity in an in vitro enzyme assay. Importantly, the Thr variant found in SMA animals showed no detectable activity. Surprisingly, in an in vivo assay the mutated gene complements the growth defect of a homologous yeast knockout strain as well as the healthy variant. This finding explains the viability of affected newborn calves and the later neuron-specific onset of the disease, which might be due to the high sensitivity of these neurons to changes in housekeeping functions. Taken together, the described mutation in FVT1 is a strong candidate for causality of SMA in cattle. This result provides an animal model for understanding the underlying mechanisms of the development of SMA and will allow efficient selection against the disease in cattle.