中国人常染色体遗传的病理性近视基因定位

A genome-wide screening for pathological myopia suggests a novel locus on chromosome 15q12-13

目的在中国人群中进行病理性近视致病基因的定位。方法1个12人的病理性近视家系（患者7名）经过研究人员告知，同意参加本研究。从每个家系成员静脉血中提取DNA，选取覆盖全基因组的330对高度杂合的微卫星DNA引物，进行基因组扫描；以常染色体显性遗传为模式，基因频率0．0133和外显率100％的条件下，运用Linkage软件进行二点连锁分析，运用Genehunter软件进行多点连锁分析。标记位点之间的遗传距离根据Genethon连锁图谱来确定。基于最低重组率原则，用cyanic软件构建单倍型。结果二点连锁分析发现15号染色体长臂上存在与病理性近视密切连锁的位点。在重组率为0的情况下，最大对数优势记分（LOD）值1．76出现在D15S1010，D15S1007和D15S1042位点；多点连锁分析也支持这个区域内存在连锁，最大NIL值为5．16。单倍型分析把这个近视眼位点局限在15q12-13上D15S1019和D15S146之间大约12cM的区间内。在已知的近视眼相关位点，包括18p11．31，12q21-23，7q36，17q21-22，4q22-q27，2q37．1，15q15-21，12q13．11-13．2，6p21．3，1q21-31，1p21和21q22．3，均没有发现明确的连锁证据。结论在15q12-13可能存在一个新的近视眼基因位点。在这个区域内至少有94个已知的基因，因此有必要对此区域进行测序寻找致病基因，这个新的基因位点的发现也证实了病理性近视存在很强的遗传异质性。

Objective Pathological myopia has a genetic background. Previous studies have mapped six loci at 18p1l. 31, 12q21-23, 7q36, 17q21-22, 4q22-q27 and 2q37. 1 in autosomal dominant （AD） pathological myopia. The aim of the present study was to map the mutate gene associated with this disorder in Chinese population. Methods A family with AD pathological myopia including 12 individuals, of which 7 members were affected, consented to participate our study. Three hundred and thirty pairs of highly heterozygous microsatellite marker primers were selected for a genome-wide screening. Two-point linkage was calculated by LINKAGE package in an autosomal dominant mode with full penctrance at gene frequency of 0. 0133. Multipoint LOD scores were calculated by use of GENEHUNTER program. Genetic distance between marker loci examined was determined on the basis of Genethon linkage map. Haplotypo analysis was performed by software of Cyrillic 2.0 based on the lowest recombination principle. Results Evidence of significant linkage was found on chromosome 15q in the family by two-point linkage analysis. The maximum LOD score was 1.76 with the markers D15S1010, D15S1007 and D15S1042 at a recombination fraction of 0.00. Multipoint linkage analysis also supported existence of linkage on this region with N-PL score 5.16. Haplotypo analysis refined this myopia locus to a 12 cM interval between D15S1019 and D155146 on 15q12-13. No evidence of linkage was found at any known myopia loci, including AD pathological myopia loci on 18p11. 31, 12q21-23, 7q36, 17q21-22, 4q22-q27 and 2q37. 1, and syndromic myopialoci on 15q15-21, 12q13. 11-13.2, 6p21.3, 1q21-31, 1p21 and 21q22.3. Conclusions Our study indicates a novel myopia locus on 15q12-13. There are 94 known genes locate on this region, screening for sequence of candidate genes within this region will be helpful to find the mutant gene. This study also provides additional support for genetic heterogeneity of this disorder.