Lattice Corneal Dystrophy Type IV (p.Leu527Arg) Is Caused by a Founder Mutation of the TGFBI Gene in a Single Japanese Ancestor
Lattice Corneal Dystrophy Type IV (p.Leu527Arg) Is Caused by a Founder Mutation of the TGFBI Gene in a Single Japanese Ancestor
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DOI：
10.1167/iovs.10-5343
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发表时间：
2010-09-01
影响因子：
4.4
通讯作者：
Kinoshita, Shigeru
中科院分区：
文献类型：
--
作者：
Fukuoka, Hideki;Kawasaki, Satoshi;Kinoshita, Shigeru
目的.格子状角膜营养不良（LCD）IV型（LCD 4）是一种迟发性角膜营养不良，在角膜深层基质层有淀粉样蛋白沉积。与其他角膜营养不良一样，这种LCD亚型也是由转化生长因子β诱导（TGFBI）基因突变（p.Leu527Arg）引起的。尽管I型LCD已在全球范围内报告，但LCD 4仅在日本人群中报告。在本研究中，进行单倍型分析，以调查这种LCD亚型是否是由创始人突变引起的。从13名不相关的LCD 4患者中提取基因组DNA样本。作为对照，还分析了96名正常志愿者的基因组DNA样本。对于单倍型分析，通过聚合酶链反应（PCR）扩增样品，TA克隆，等温扩增，并进行针对突变位点的1-碱基引物延伸测定（c. 1580 T> G）和六个已知的单核苷酸多态性（SNP; rs 4669、rs 2072239、rs7727725、rs 17689879、rs6871571和rs3792900），它们位于突变位点附近。单倍型分析显示，所有携带疾病的等位基因从13例LCD 4患者共享一个相同的单倍型，而非携带疾病的等位基因从正常志愿者和LCD 4患者表现出四个单倍型。携带和非携带疾病等位基因的单倍型分布差异有统计学意义。这项研究的结果强烈表明，LCD 4是由一个单一的日本祖先中发生的TGFBI基因的创始人突变引起的。（Invest Ophthalmol维斯科学。2010;51：4523-4530）DOI：10.1167/iovs.10-5343
PURPOSE. Lattice corneal dystrophy (LCD) type IV (LCD4) is a late-onset corneal dystrophy with amyloid deposition at the deep stromal layer of cornea. As with other corneal dystrophies, this LCD subtype is also caused by a mutation (p. Leu527Arg) of the transforming growth factor, beta-induced (TGFBI) gene. Although LCD type I has been reported worldwide, LCD4 has been reported only in the Japanese population. In the present study, a haplotype analysis was performed to investigate whether this LCD subtype is caused by a founder mutation.METHODS. Genomic DNA samples were extracted from 13 unrelated patients with LCD4. As a control, genomic DNA samples from 96 normal volunteers were also analyzed. For the haplotype analysis, the samples were amplified by polymerase chain reaction (PCR), TA-cloned, isothermally amplified, and subjected to a 1-base primer extension assay against a mutation site (c. 1580T > G) and six known single-nucleotide polymorphisms (SNPs; rs4669, rs2072239, rs7727725, rs17689879, rs6871571, and rs3792900), which are located adjacent to the mutation site.RESULTS. The haplotype analysis revealed that all the disease-carrying alleles from the 13 LCD4 patients shared an identical haplotype, whereas non-disease-carrying alleles from the normal volunteers and the LCD4 patients exhibited four haplotypes. There was a statistically significant difference in the haplotype distribution between the disease-carrying and the non-disease-carrying alleles.CONCLUSIONS. The findings of this study strongly indicate that LCD4 was caused by a founder mutation of the TGFBI gene that occurred in a single Japanese ancestor. (Invest Ophthalmol Vis Sci. 2010;51:4523-4530) DOI:10.1167/iovs.10-5343