Functional analysis of Homeobox gene responsible for congenital hereditary ptosis and isolation of its associated protein

我们首先认为DMBX1是一个很强的候选基因，它位于D1S2733的2.6Mb端粒一侧。STRP标记D1S2733是Engle等人定义的CADIDATE基因座的末端标记。我们在1例先天性遗传性上睑下垂(CHP)患者中发现了Missese突变。然而，我们还发现，在患者的非患病父亲和弟弟中，DMBX1基因不太可能是CHP的致病基因。我们改变了研究目标，在一个大家族中进行连锁分析，以寻找新的CHP基因座。我们在15个成员中使用ABI棱镜连锁图谱集-MD10，其中包括4个受影响的个体。用Fastlink Ver.4.1P或GeneHunter软件中的MLINK软件进行LOD评分计算。6个标记D1S2697(1p)、、D1S255(1p)、、D1S484(1q)、D5S630(5p)、D7S669(7q)和D14S276(14q)显示较高的LOD值，表明可能存在连锁。我们在这些标记周围设置了另一个STRP标记来进行单倍型分析。我们发现1p35.3-36.1和14q21.1-23.2这两个区域是可能的候选基因座，但我们不能将其定义为一个区域。一些成员可能有突变的单倍型，但没有CHP表型，提示该家族存在不完全外显。我们将重新评估该家族成员的表型，并对新的家系进行连锁分析，以确定CHP的候选基因座。

We firstly thought DMBX1 is strong candidate which is located 2.6 Mb telomeric side of D1S2733. The STRP marker, D1S2733,is distal marker Engle et al., defined the cadidate locus. We found missnese mutation in one patient with congenital hereditary ptosis(CHP). We also found, however, this missense mutaiton in non-affected father and younger brother of the patients, DMBX1 gene would not likely to be causative gene for CHP.We changed our research aim to do linkage analysis in one large family to fined new locus for CHP. We used ABI Prism Linkage Mapping Set-MD10 in 15 members including 4 affected individuals. LOD score calculation was performed with MLINK software in FASTLINK ver.4.1P or Genehunter software. Six markers, D1S2697 (1p)、D1S255 (1p)、D1S484 (1q), D5S630 (5p), D7S669 (7q), and D14S276 (14q) showed relatively high LOD score indication possible linkage. We set another STRP markers around these markers to perform haplotype analysis. We found two regions, 1p35.3-36.1 and 14q21.1-23.2,are possible candidate loci, but we could not define to one region. Some members have possible mutant haplotype without CHP phenotype and suggest incomplete penetrance in this family. We would re-evaluate phnotypes of members in this family and perform linkage analysis of new family to confirm the candidate locus for CHP.