Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p
Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p
复制标题
DOI：
10.1016/j.ajhg.2009.12.001
复制
发表时间：
2010-01-08
影响因子：
9.8
通讯作者：
Katsanis, Nicholas
中科院分区：
文献类型：
--
作者：
Riazuddin, S. Amer;Zaghloul, Norann A.;Katsanis, Nicholas
Fuchs角膜营养不良(FCD)是一种角膜内皮退行性遗传性疾病，是美国角膜移植最常见的原因之一。尽管FCD的患病率很高(4%，40岁以上)，但其潜在的遗传基础在很大程度上是未知的。在这里，我们报告了在一组晚发性FCD患者中TCF8的错义突变，TCF8是一种转录因子，其单倍性不足导致后部多形性角膜营养不良(PPCD)。与导致PPCD的突变不同，所有这些突变都是空的，FCD相关突变编码罕见的错义变化，通过体内互补分析表明会导致功能丧失。重要的是，在一个大型、多代FCD家系中分离出一个复发的p.Q840P突变，表明该等位基因对发病是充分的，但不是必需的。以840P等位基因的存在为条件进行全基因组扫描，在9p染色体上发现了另一个晚发性FCD基因座，而单倍型分析表明，TCF8等位基因的存在和9p上的疾病单倍型导致了严重的FCD表现，预后不良。我们的数据表明，PPCD和FCD是同一疾病连续体的等位基因变体，导致角膜营养不良的基因之间的遗传相互作用可以调节表型的表达。
Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4%, over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes Suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allele variants of the same disease Continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.