Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy
Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy
复制标题
DOI：
10.1167/iovs.04-0937
复制
发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Magovern, M
中科院分区：
文献类型：
--
作者：
Gottsch, JD;Sundin, OH;Magovern, M
目的.探讨遗传性Fuchs角膜营养不良（FCD）的遗传基础和表型。来自血液的DNA用于具有串联重复多态性的全基因组连锁扫描。突变检测包括PCR扩增外显子测序。对FCD家族进行临床评估，并根据Krachmer严重程度量表进行分级。共聚焦镜面显微镜观察到内皮细胞的形态学，后弹力膜的小突起是FCD的特征。Magovern在1979年首次报道了常染色体显性遗传家系的1p34.3-p32连锁。所有21例FCD和1例后部多形性营养不良患者均为L450 W杂合子，L450 W是COL 8A 2基因中的一种新点突变。在62例独立的家族性FCD病例中，没有一例具有先前报道的COL 8A 2突变。COL 8A 2患者的角膜滴液较小，呈圆形，与内皮细胞中心相关。这与常见的FCD形成对比，在FCD中，滴液较大，尖锐，最初位于内皮细胞的边缘。L450 W家族FCD患者的年龄和疾病严重程度表明，其发病发生在婴儿期，而其他62个家族中的201例FCD患者的平均发病年龄估计为50岁。一种新的致病性L450 W COL 8A 2突变被确定，其高度独特的病理特征。这表明COL 8A 2突变引起FCD的罕见亚型。这项研究还提供了第一个直接证据，表明COL 8A 2-FCD在25年内从早期发展到晚期，这一速度与晚发型FCD的估计速度相似。
PURPOSE. To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD).METHODS. DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD.RESULTS. Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families.CONCLUSIONS. A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD.