Brittle Cornea Syndrome ZNF469 Mutation Carrier Phenotype and Segregation Analysis of Rare ZNF469 Variants in Familial Keratoconus
Brittle Cornea Syndrome ZNF469 Mutation Carrier Phenotype and Segregation Analysis of Rare ZNF469 Variants in Familial Keratoconus
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DOI：
10.1167/iovs.14-15792
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发表时间：
2015-01-01
影响因子：
4.4
通讯作者：
Hardcastle, Alison J.
中科院分区：
文献类型：
--
作者：
Davidson, Alice E.;Borasio, Edmondo;Hardcastle, Alison J.
目的.脆性角膜综合征1（BCS 1）是一种罕见的隐性疾病，其特征是角膜和巩膜极度变薄，由ZNF 469突变引起。圆锥角膜是一种比较常见的疾病，其特征是角膜进行性变薄和扩张。圆锥角膜的病因是复杂的，尚未了解，但罕见的ZNF 469变异最近与疾病有关。我们调查了已知致病性ZNF 469突变的BCS 1携带者的表型，并招募了圆锥角膜聚集的家系，以确定ZNF 469的罕见变异是否与疾病分离。招募患者和家庭成员，并进行全面的眼前节检查，包括角膜地形图。捐献血样并提取基因组DNA。PCR扩增ZNF 469的编码序列和剪接位点，并进行桑格测序。四名携带三种BCS 1相关ZNF 469功能丧失突变的携带者（p. [Glu1392Ter]，p. [Gln1930Argfs*6]，p. [Gln1930fs*133]）进行检查，无圆锥角膜。一名携带者具有BCS 1的部分渗透特征，包括关节过度活动。11个圆锥角膜家系的ZNF 469基因测序鉴定出9个罕见（次要等位基因频率[MAF]）
PURPOSE. Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease.METHODS. Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced.RESULTS. Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF]