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

<IDENTIFICATION OF SUBMICROSCOPIC DELETION BY SNAP ANALYSIS WITHIN SHOX GENE>我们已经报道了SHOX单倍不足主要是由涉及整个SHOX基因的假常染色体亚显微缺失引起的，而不是基因内突变。尽管这表明FISH分析在检测SHOX单倍不足中的重要性，但FISH分析仍然仅在有限的机构中是可能的。2002年，我们在SHOX基因中发现了8个SNPs，发现这8个SNPs不存在连锁不平衡。因此，如果检测到单个SNP的杂合性，则用DNA样品进行的8个SNP分析可以排除亚显微缺失，并且如果所有8个SNP都以明显纯合状态存在，则也可以指示亚显微缺失。因此，我们可以开发一种新的诊断方法，使用DNA样品检测亚显微缺失。<GROWTH PATTERN AND BODY PROPORTION ANALYSIS IN A PATIENT WITH SHOX HAPLOINSUFFICIENCY AND NORMAL OVARIAN FUNCTION>我们可以观察到一个SHOX单倍性不足和卵巢功能正常的女性的长期生长模式和身体比例的变化。这名女孩在青春期表现出严重的生长障碍，这与中肢外观有关。青春期生长峰值小于正常女孩，月经初潮时突然停止生长。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，虽然它们让人想起特纳女性，但在中肢畸形中比特纳女性更容易发生。因此，特纳女性的生长特征归因于SHOX单倍不足和卵巢雌激素缺乏。<ISOLATION OF SHOX C-DNA>由于SHOX同源物在小鼠中不存在，因此转基因小鼠实验可用于分析SHOX的生物学效应。作为第一步，我们可以获得SHOX基因的近全长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.