Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts
Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts
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DOI：
10.1194/jlr.m400462-jlr200
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发表时间：
2005-06-01
影响因子：
6.5
通讯作者：
Herman, GE
中科院分区：
文献类型：
--
作者：
Cunningham, D;Swartzlander, D;Herman, GE
已经描述了七种角鲨烯后胆固醇生物合成的人类疾病。其中一种是先天性半侧发育不良伴鱼鳞状痣和肢体缺陷综合征(CHILD)，是由编码类固醇脱氢酶的X-连锁基因NADH类固醇脱氢酶(NSDHL)突变所致。裸斑(BPA)小鼠携带一系列突变的小鼠Nsdh1基因等位基因，其中BPA(1H)代表零等位基因。杂合的BPA(1H)雌鼠表现出皮肤和骨骼的异常，其分布反映了随机的X失活，而半合子的雄性胚胎在胚胎10.5天之前死亡。为了研究与胆固醇生物合成紊乱相关的缺陷的分子基础，进行了基因芯片分析，比较了表达BPA(1H)等位基因的胚胎成纤维细胞和野生型(Wt)细胞的基因表达。从正常血清或去脂血清(LDS)中生长的细胞中标记的cDNA与包含22,000个小鼠基因的微阵列杂交。在44个在LDS中生长的BPA(1H)细胞中高表达的基因中，11个参与胆固醇的生物合成，7个参与脂肪酸的合成，3个(Srebp2，Insig1和Orf11)编码固醇调节蛋白，2个(Ldlr和StarD4)是脂类转运蛋白。在剩下的21个基因中，有16个是已知基因，其中一些以前与胆固醇稳态或脂质介导的信号转导有关，5个是未鉴定的cdna克隆。
Seven human disorders of postsqualene cholesterol biosynthesis have been described. One of these, congenital hemidysplasia with ichthyosiform nevus and limb defects ( CHILD) syndrome, results from mutations in the X-linked gene NADH sterol dehydrogenase-like (NSDHL) encoding a sterol dehydrogenase. A series of mutant alleles of the murine Nsdhl gene are carried by bare patches (Bpa) mice, with Bpa(1H) representing a null allele. Heterozygous Bpa(1H) females display skin and skeletal abnormalities in a distribution reflecting random X inactivation, whereas hemizygous male embryos die before embryonic day 10.5. To investigate the molecular basis of defects associated with perturbations in cholesterol biosynthesis, microarray analysis was performed comparing gene expression in embryonic fibroblasts expressing the Bpa(1H) allele versus wild-type (wt) cells. Labeled cDNAs from cells grown in normal serum or lipid-depleted serum ( LDS) were hybridized to microarrays containing 22,000 mouse genes. Among 44 genes that showed higher expression in the Bpa(1H) versus wt cells grown in LDS, 11 function in cholesterol biosynthesis, 7 are involved in fatty acid synthesis, 3 (Srebp2, Insig1, and Orf11) encode sterol-regulatory proteins, and 2 (Ldlr and StarD4) are lipid transporters. Of the 21 remaining genes, 16 are known genes, some of which have been implicated previously in cholesterol homeostasis or lipid-mediated signaling, and 5 are uncharacterized cDNA clones.