Weiss Jayne S, Kruth Howard S, Kuivaniemi Helena, Tromp Gerard, Karkera Jayaprakash, Mahurkar Sunil, Lisch Walter, Dupps William J, White Peter S, Winters R Scott, Kim Chaesik, Rapuano Christopher J, Sutphin John, Reidy Jim, Hu Fung-Rong, Lu Da Wen, Ebenezer Neil, Nickerson Michael L
Kresge Eye Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Am J Med Genet A. 2008 Feb 1;146A(3):271-83. doi: 10.1002/ajmg.a.32201.
Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E.
施奈德结晶性角膜营养不良（SCCD）是一种罕见的常染色体显性疾病，其特征是由于胆固醇和磷脂异常沉积导致角膜进行性混浊。最近，发现位于1p36染色体上的UBIAD1基因有六种不同突变可导致SCCD。本文的目的是进一步明确SCCD的突变谱，并确定对UBIAD1蛋白活性的结构和功能影响。对来自14个SCCD家系的36名个体的样本进行了DNA测序。一名受影响个体为非裔美国人，此前该种族群体中尚未报道过SCCD。我们在所有14个家系中鉴定出了UBIAD1突变，其中有30名受影响个体和6名未受影响个体。鉴定出了八种不同的UBIAD1突变，其中5种是新的（外显子1中的L121F、D118G和S171P，外显子2中的G186R和D236E）。在四个同时有受影响和未受影响个体DNA样本的家系中，D118G、G186R、T175I和G177R突变与SCCD共分离。结合我们之前的报告，我们在20个无关家系中鉴定出了UBIAD1中的基因突变，其中10个家系（包括此处报告的5个家系）有N102S突变。结果表明，N102S可能是一个突变热点，因为受影响的家系无关，包括白种人和亚洲个体。除了T175I突变表现出明显的弥漫性角膜混浊（通常无角膜结晶）外，没有基因型与表型的相关性。蛋白质分析揭示了SCCD突变可能影响UBIAD1功能、配体结合以及与结合伴侣（如载脂蛋白E）相互作用的结构和功能影响。
