Lathosterolosis:: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency
Lathosterolosis:: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency
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DOI：
10.1093/hmg/ddg172
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发表时间：
2003-07-01
影响因子：
3.5
通讯作者：
Porter, FD
中科院分区：
文献类型：
--
作者：
Krakowiak, PA;Wassif, CA;Porter, FD
在胆固醇合成的倒数第二步中，脂甾醇5-去饱和酶催化脂甾醇转化为7-脱氢胆固醇。胆固醇合成的先天性错误是一组人类畸形综合征的基础，包括Smith-Lemli-Opitz综合征、纤维固醇沉着症、CHILD综合征、CDPX 2和纤维硬结病。我们破坏了Lathosterol 5-去饱和酶基因（Sc 5d），以进一步了解这些疾病的病理生理过程，并深入了解相应的人类疾病。sc 5d（-/-）幼仔是死产的，具有升高的脂甾醇和降低的胆固醇水平，具有颅面缺陷，包括腭裂和小颌畸形，以及肢体图案缺陷。在Sc 5d（-/-）小鼠中发现的许多畸形与受损的刺猬信号一致，并且似乎是胆固醇降低而不是脂甾醇增加的结果。一名最初被描述为非典型SLOS伴粘脂沉积症的患者，经生化和分子分析显示患有脂膜硬化症。我们在该患者中发现了一种SC 5D纯合突变（137 A>C，Y 46 S）。骨脂增多症表型的一个独特方面是畸形综合征与细胞内储存缺陷的组合。
Lathosterol 5-desaturase catalyzes the conversion of lathosterol to 7-dehydrocholesterol in the next to last step of cholesterol synthesis. Inborn errors of cholesterol synthesis underlie a group of human malformation syndromes including Smith-Lemli-Opitz syndrome, desmosterolosis, CHILD syndrome, CDPX2 and lathosterolosis. We disrupted the lathosterol 5-desaturase gene (Sc5d ) in order to further our understanding of the pathophysiological processes underlying these disorders and to gain insight into the corresponding human disorder. Sc5d(-/-) pups were stillborn, had elevated lathosterol and decreased cholesterol levels, had craniofacial defects including cleft palate and micrognathia, and limb patterning defects. Many of the malformations found in Sc5d(-/-) mice are consistent with impaired hedgehog signaling, and appear to be a result of decreased cholesterol rather than increased lathosterol. A patient initially described as atypical SLOS with mucolipidosis was shown to have lathosterolosis by biochemical and molecular analysis. We identified a homozygous mutation of SC5D (137A>C, Y46S) in this patient. An unique aspect of the lathosterolosis phenotype is the combination of a malformation syndrome with an intracellular storage defect.