CLARIFICATION OF CLINICAL ROLE AND GROWTH REGULATION MECHANISM OF THE SHOX GENE ON THE HUMAN PSEUDOAUTOSOMAL REGION

SNAP分析鉴定Shox基因亚显微缺失我们曾报道，Shox单倍体缺失主要是由涉及整个Shox基因的伪常染色体亚显微缺失引起的，而不是基因内的突变。虽然这表明FISH分析在检测Shox单倍体不足方面的重要性，但FISH分析仍然只可能在有限的机构中进行。2002年，我们在Shox基因中发现了8个SNPs，发现这8个SNPs没有表现出连锁不平衡。因此，对DNA样本的8个SNP分析可以排除亚微观缺失，如果检测到单个SNP的杂合性，也可以指示亚微观缺失，如果所有8个SNP都存在明显的纯合子状态。因此，我们可以开发一种新的诊断方法，利用DNA样本来检测亚显微缺失。卵巢功能正常的Shox单倍体功能不全患者的生长模式和体比例分析。我们可以观察Shox单倍体功能不全而卵巢功能正常的女性的长期生长模式和体比例的变化。这个女孩表现出严重的青春期发育障碍，这与中胚层外观有关。她的青春期生长峰值速度小于正常女孩，随着月经初潮的到来，她突然停止了生长。她有正常的头围和手长。这种长期的生长模式和身体比例的变化，尽管让人想起特纳女性的那些，但在中胚胎症中比特纳女性更严重。因此，Turner雌鼠的生长特征被归因于Shox单倍体功能不全和卵巢雌激素缺乏。由于Shox同源基因在小鼠中缺失，转基因小鼠实验对于分析Shox的生物学效应是有用的。作为第一步，我们可以获得Shox基因的几乎全长的c-DNA。

<IDENTIFICATION OF SUBMICROSCOPIC DELETION BY SNAP ANALYSIS WITHIN SHOX GENE>We have reported that SHOX haploinsufficiency is primarily caused by pseudoautosomal submicroscopic deletions involving the entire SHOX gene, rather than the intragenic mutations. Although this indicates the importance of FISH analysis in the detection of SHOX haploinsufficiency, FISH analysis is still possible only in a limited institutions. In the year 2002, we have identified 8 SNPs within the SHOX gene, and found that the 8 SNPs do not show linkage disequibrium. Thus, the 8 SNP analysis with DNA samples can exclude a submicroscopic deletion if heterozygosity is detected for a single SNP, and also can indicate submicroscopic deletion if all the 8 SNPs are present in an apparently homozygous state. Thus, we could develop a novel diagnostic method with use of DNA samples for the detection of a submicroscopic deletion.<GROWTH PATTERN AND BODY PROPORTION ANALYSIS IN A PATIENT WITH SHOX HAPLOINSUFFICIENCY AND NORMAL OVARIAN FUNCTION>We could observe a long-term growth pattern and a change in body proportion in a female with SHOX haploinsufficnecy and normal ovarian function. This girl exhibited severe growth failure with puberty that is associated with mesomelic appearance. Her peak growth velocity during puberty was smaller than that of normal girls, and she suddently stoped growing with menarche. She had normal head circumference and hand length. This long-term growth pattern and change in body proportion, though they are reminiscent of those of Turner females, are severer in mesomelia than Turner females. Thus, growth characteristics of Turner females are ascribed to SHOX haploinsufficiency and ovarian estrogen deficiency.<ISOLATION OF SHOX C-DNA>Since SHOX homolog is absent in mice, transgenic mouse experiments are useful in analyzing the biological effects of SHOX. As a first step, we could obtain nearly full length c-DNA of the SHOX gene.