Munier F L, Korvatska E, Djemaï A, Le Paslier D, Zografos L, Pescia G, Schorderet D F
Unit of Molecular Genetics, CHUV, Lausanne, Switzerland.
Nat Genet. 1997 Mar;15(3):247-51. doi: 10.1038/ng0397-247.
Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies. Clinically, they show progressive opacification of the cornea leading to severe visual handicap. The nature of the deposits remains unknown in spite of amyloid aetiology ascribed to the last two. We generated a YAC contig of the linked region and, following cDNA selection, recovered the beta ig-h3 gene. In six affected families we identified missense mutations. All detected mutations occurred at the CpG dinucleotide of two arginine codons: R555W in one CDGG1, R555Q in one CDRB, R124C in two CDL1 and R124H in two ACD families. This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of beta ig-h3) forms amyloidogenic intermediates that precipitate in the cornea. Our data establish a common molecular origin for the 5q31-linked corneal dystrophies.
颗粒状营养不良格罗诺伊I型（CDGG1）、 Reis-Bücklers型（CDRB）、格子状I型（CDL1）和阿韦利诺型（ACD）是四种与5q31连锁的人类常染色体显性遗传性角膜营养不良。临床上，它们表现为角膜进行性混浊，导致严重视力障碍。尽管后两种疾病被认为是淀粉样变病因，但沉积物的性质仍然未知。我们构建了该连锁区域的酵母人工染色体（YAC）重叠群，并通过cDNA筛选，获得了βig-h3基因。在六个患病家族中，我们鉴定出了错义突变。所有检测到的突变都发生在两个精氨酸密码子的CpG二核苷酸处：一个CDGG1家族中的R555W、一个CDRB家族中的R555Q、两个CDL1家族中的R124C以及两个ACD家族中的R124H。由于后两种疾病的特征是淀粉样沉积物，这表明R124突变的角蛋白上皮素（βig-h3的产物）形成了在角膜中沉淀的淀粉样生成中间体。我们的数据为5q31连锁的角膜营养不良建立了共同的分子起源。
