Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause schnyder crystalline corneal dystrophy
Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause schnyder crystalline corneal dystrophy
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DOI：
10.1167/iovs.07-0845
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发表时间：
2007-11-01
影响因子：
4.4
通讯作者：
Nickerson, Michael L.
中科院分区：
文献类型：
--
作者：
Weiss, Jayne S.;Kruth, Howard S.;Nickerson, Michael L.
目的.施奈德结晶性角膜营养不良（SCCD; MIM 121800）是一种罕见的常染色体显性遗传疾病，其特征是角膜中胆固醇和磷脂沉积异常增加，导致进行性角膜混浊。虽然SCCD已被映射到标记D1 S1160和D1 S1635之间的遗传区间，但对先前未受影响的个体的重新分类将区间扩大到D1 S2667，并包括9个额外的基因。分析了可能参与脂质代谢和/或在角膜中表达的三个候选基因。DNA样本来自6个临床确诊的SCCD家庭。通过基于PCR的DNA测序对FRAP 1、ANGPTL 7和UBIAD 1进行分析，以检查蛋白质编码区、RNA剪接点和5 '非翻译区（UTR）外显子。在FRAP 1或ANGPTL 7基因中未发现致病突变。在所有6个家族中均发现了UBIAD 1突变：5个家族具有相同的N102 S突变，1个家族具有G177 R突变。蛋白质结构的预测表明，异戊二烯基转移酶结构域和几个跨膜螺旋受到这些突变的影响。每个突变与疾病共分离的四个家庭的DNA样本，从受影响和未受影响的个人。在100个对照DNA样本（200条染色体）中未观察到突变。在6个SCCD家族中检测到UBIAD 1基因的非同义突变，并在氨基酸N102处观察到潜在的突变热点。这些突变预计会干扰UBIAD 1蛋白的功能，因为它们位于高度保守和结构重要的结构域。
PURPOSE. Schnyder crystalline corneal dystrophy ( SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed.METHODS. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5 ' untranslated region ( UTR) exons.RESULTS. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples ( 200 chromosomes).CONCLUSIONS. Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains.