Suzuki O T, Sertié A L, Der Kaloustian V M, Kok F, Carpenter M, Murray J, Czeizel A E, Kliemann S E, Rosemberg S, Monteiro M, Olsen B R, Passos-Bueno M R
Departamento de Biologia, Instituto de Biociências, São Paulo, Brasil.
Am J Hum Genet. 2002 Dec;71(6):1320-9. doi: 10.1086/344695. Epub 2002 Nov 1.
Knobloch syndrome (KS) is a rare disease characterized by severe ocular alterations, including vitreoretinal degeneration associated with retinal detachment and occipital scalp defect. The responsible gene, COL18A1, has been mapped to 21q22.3, and, on the basis of the analysis of one family, we have demonstrated that a mutation affecting only one of the three COL18A1 isoforms causes this phenotype. We report here the results of the screening of both the entire coding region and the exon-intron boundaries of the COL18A1 gene (which includes 43 exons), in eight unrelated patients with KS. Besides 20 polymorphic changes, we identified 6 different pathogenic changes in both alleles of five unrelated patients with KS (three compound heterozygotes and two homozygotes). All are truncating mutations leading to deficiency of one or all collagen XVIII isoforms and endostatin. We have verified that, in exon 41, the deletion c3514-3515delCT, found in three unrelated alleles, is embedded in different haplotypes, suggesting that this mutation has occurred more than once. In addition, our results provide evidence of nonallelic genetic heterogeneity in KS. We also show that the longest human isoform (NC11-728) is expressed in several tissues (including the human eye) and that lack of either the short variant or all of the collagen XVIII isoforms causes similar phenotypes but that those patients who lack all forms present more-severe ocular alterations. Despite the small sample size, we found low endostatin plasma levels in those patients with mutations leading to deficiency of all isoforms; in addition, it seems that absence of all collagen XVIII isoforms causes predisposition to epilepsy.
诺布罗赫综合征（KS）是一种罕见疾病，其特征为严重的眼部改变，包括与视网膜脱离和枕部头皮缺损相关的玻璃体视网膜变性。致病基因COL18A1已被定位到21q22.3，并且基于对一个家系的分析，我们已证明仅影响三种COL18A1异构体之一的突变会导致这种表型。我们在此报告对8名无关的KS患者的COL18A1基因（包含43个外显子）的整个编码区及外显子 - 内含子边界进行筛查的结果。除了20种多态性变化外，我们在5名无关的KS患者（3名复合杂合子和2名纯合子）的两个等位基因中鉴定出6种不同的致病变化。所有这些都是截短突变，导致一种或所有胶原蛋白XVIII异构体和内皮抑素缺乏。我们已证实，在41号外显子中，在三个无关的等位基因中发现的缺失c3514 - 3515delCT嵌入不同的单倍型中，这表明该突变已发生不止一次。此外，我们的结果提供了KS中非等位基因遗传异质性的证据。我们还表明，人类最长的异构体（NC11 - 728）在几种组织（包括人眼）中表达，并且缺乏短变体或所有胶原蛋白XVIII异构体都会导致相似的表型，但那些缺乏所有形式的患者眼部改变更严重。尽管样本量小，但我们发现那些因突变导致所有异构体缺乏的患者血浆内皮抑素水平较低；此外，似乎所有胶原蛋白XVIII异构体的缺失会导致易患癫痫。
