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

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<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.