Genome-wide linkage analysis and mutation analysis of hereditary congenital blepharoptosis in a Japanese family
Genome-wide linkage analysis and mutation analysis of hereditary congenital blepharoptosis in a Japanese family
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DOI：
10.1007/s10038-007-0214-6
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发表时间：
2008-01-01
影响因子：
3.5
通讯作者：
Yoshiura, Koh-ichiro
中科院分区：
文献类型：
--
作者：
Nakashima, Mitsuko;Nakano, Motoi;Yoshiura, Koh-ichiro
遗传性先天性上睑下垂（PTOS）被定义为上眼睑下垂，没有任何其他伴随症状，与综合征性上睑下垂相区别。之前的两次连锁分析将一个 PTOS 位点 (PTOS1) 分配给 1p32-p34.1，另一个 (PTOS2) 分配给 Xq24-q27.1。此外，在染色体平衡易位t(1;8) (p34.3;q21.12)的散发病例中，发现ZFHX4（锌指同源结构域4）基因在8q21.12断点处被破坏，但在1p34.3断点处没有基因，表明存在第三个PTOS位点（PTOS1） 8q21.12。我们在日本 PTOS 家族中进行了全基因组连锁分析，并计算了外显率降低的两点和多点对数 (LOD) 评分。单倍型分析给出了三个候选疾病责任区，即8q21.11-q22.1、12q24.32-q24.33和14q21.1-q23.2。尽管家族规模太小而无法定义其中之一，但 8q21.11-q22.1 是一个可能的候选区域，因为它包含之前报道的上面的易位断点。因此，我们对 ZFHX4 进行了突变、Southern 印迹和甲基化分析，但未能在该家族中发现任何疾病特异性的变化。尽管如此，我们的数据可能支持 PTOS1 的本地化。
Hereditary congenital ptosis (PTOS) is defined as drooping of the upper eyelid without any other accompanying symptoms and distinguished from syndromic blepharoptosis. Two previous linkage analyses assigned a PTOS locus (PTOS1) to 1p32-p34.1 and another (PTOS2) to Xq24-q27.1. In addition, in a sporadic case with a balanced chromosomal translocation t(1;8) (p34.3;q21.12), the ZFHX4 (zinc finger homeodomain 4) gene was found to be disrupted at the 8q21.12 breakpoint, but there was no gene at the 1p34.3 breakpoint, suggesting the existence of the third PTOS locus (PTOS1) at 8q21.12. We carried out a genome-wide linkage analysis in a Japanese PTOS family and calculated two-point and multipoint log of odds (LOD) scores with reduced penetrance. Haplotype analysis gave three candidate disease-responsible regions, i.e., 8q21.11-q22.1, 12q24.32-q24.33, and 14q21.1-q23.2. Although the family size is too small to define one of them, 8q21.11-q22.1 is a likely candidate region, because it contains the previously reported translocation breakpoint above. We thus performed mutation, Southern-blot and methylation analyses of ZFHX4 but could not find any disease-specific change in the family. Nevertheless, our data may support the localization of PTOS1.