Tang Yongming G, Rabinowitz Yaron S, Taylor Kent D, Li Xiaohui, Hu Mingshu, Picornell Yoana, Yang Huiying
Medical Genetics Institute, Cedars-Sinai Medical Center, 665W 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Genet Med. 2005 Jul-Aug;7(6):397-405. doi: 10.1097/01.gim.0000170772.41860.54.
Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogeneous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomal-dominant pedigree to identify disease loci for keratoconus.
A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at approximately 10 cM density. This was followed by fine mapping at approximately 2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2.
Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance = 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99-119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8.2 Mbp physical distance) between markers D5S2499 and D5S495.
These results indicate a promising new locus for keratoconus in this pedigree. Because of the heterogeneous nature of keratoconus, this locus may be specific to familial autosomal-dominant keratoconus. Nevertheless, the identification of this locus may provide new insights into the pathogenesis of keratoconus.
圆锥角膜是一种角膜营养不良疾病，发病率为两千分之一，是西方发达国家角膜移植的主要原因。临床观察和家系分析均表明基因在其发病机制中起主要作用。圆锥角膜具有遗传异质性，最常见为散发性，但也有隐性或显性遗传模式的报道。我们研究了一个四代常染色体显性遗传家系，以确定圆锥角膜的疾病基因座。
对27名家庭成员进行两阶段全基因组扫描。首先，使用沿22条常染色体分布、密度约为10 cM的343个微卫星标记进行连锁分析。随后，在提示连锁的区域以约2 cM的密度进行精细定位。使用GeneHunter2进行多点连锁分析。
在5号染色体5q14.1-q21.3区域82至112 cM处观察到初步扫描提示连锁的证据，最大对数优势分数（LOD）为3.48（外显率=0.5）。通过以1至3 cM间隔测试另外11个微卫星标记进行精细定位，发现了一个更窄且更高的峰值（99-119 cM），LOD为3.53。通过单倍型重组分析，圆锥角膜的推定基因座进一步缩小到标记D5S2499和D5S495之间的6 cM区域（物理距离8.2 Mbp）。
这些结果表明该家系中圆锥角膜有一个有前景的新基因座。由于圆锥角膜的异质性，该基因座可能特定于家族性常染色体显性圆锥角膜。尽管如此，该基因座的鉴定可能为圆锥角膜的发病机制提供新的见解。
