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

阐明SHOX基因对人类伪常染色体区的临床作用和生长调节机制

• 批准号: 12470171
• 负责人: MATSUO Nobutake
• 金额: $ 7.62万
• 依托单位: NATIONAL CENTER FOR CHILD HEALTH AND DEVELOPMENT (2001-2002)Keio University (2000)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470171/
• 关键词: SHOX; SEX CHROMOSOME; HAPLOINSUFFICIENCY; TURNER SKELETAL FEATURES; SHORT STATURE; GONADAL FUNCTION; LYMPHOEDEMA; SNP; 成長パターン; 座高; 下肢長比; dyscondrosteosis; Langer type skeletal dysplasia; 量効果; X染色体短腕欠失

<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.

<通过SHOX基因内的SNAP分析鉴定亚显微缺失>我们报道了SHOX单倍体不足主要是由涉及整个SHOX基因的伪常染色体亚显微缺失而不是基因内突变引起的。尽管这表明了 FISH 分析在检测 SHOX 单倍体不足方面的重要性，但 FISH 分析仍然只能在有限的机构中进行。 2002年，我们鉴定了SHOX基因内的8个SNP，发现这8个SNP不存在连锁不平衡。因此，如果检测到单个 SNP 的杂合性，则对 DNA 样品进行 8 个 SNP 分析可以排除亚显微缺失，如果所有 8 个 SNP 都以明显纯合的状态存在，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 样本来检测亚显微缺失。<SHOX 单倍体不足且卵巢功能正常的患者的生长模式和身体比例分析>我们可以观察长期生长模式并SHOX 单倍体不足且卵巢功能正常的女性身体比例发生变化。这个女孩在青春期表现出严重的生长障碍，这与中粒外观有关。她在青春期的峰值生长速度比正常女孩要小，并且随着初潮突然停止生长。她的头围和手长正常。这种长期的生长模式和身体比例的变化，虽然让人想起特纳雌性，但在中体中比特纳雌性更严重。因此，特纳雌性的生长特征归因于SHOX单倍体不足和卵巢雌激素缺乏。<SHOX C-DNA的分离>由于小鼠中不存在SHOX同系物，因此转基因小鼠实验可用于分析SHOX的生物学效应。第一步，我们可以获得 SHOX 基因的几乎全长的 c-DNA。

项目成果

Ogata T, et al.: "Turner syndrome and Xp deletions : clinical and molecular studies in 47 patients"Journal of Clinical Endocrinology and Metabolism. 86(11). 5498-5508 (2001)

Ogata T 等人：“特纳综合征和 Xp 缺失：47 名患者的临床和分子研究”临床内分泌与代谢杂志。

Ogata T, et al.: "Genetic evidence for a novel gene (s) involved in urogenital development on 10q26."Kidney International. 58(6). 2281-2290 (2000)

Ogata T 等人：“涉及 10q26 泌尿生殖发育的新基因的遗传证据。”肾脏国际。

SHOX defects in idiopathic short stature

特发性身材矮小症的 SHOX 缺陷

• 发表时间: 2002
• 期刊: Journal of Pediatric Endocrinology and Metabolism 15(12)
• 作者: Fujita H;Kosaki K;Matsuo N;et al.;Ogata T;Ogata T
• 通讯作者: Ogata T

SHOX haploinsufficiency and its modifying factors

SHOX单倍体不足及其调节因素

• 发表时间: 2002
• 期刊: Journal of Pediatric Endocrinology and Metabolism 15(12)
• 作者: Fujita H;Kosaki K;Matsuo N;et al.;Ogata T
• 通讯作者: Ogata T

SHOX haploinsufficiency and its modifying factors.

SHOX 单倍体不足及其调节因素。

• 发表时间: 2002
• 期刊: Journal of Pediatric Endocrinology and Metabolism 15(12)
• 作者: Fujita H;Kosaki R;Yoshihashi H;Ogata T;Tomita M;Takahashi T;Matsuo N;Kosaki K.;Ogata T.
• 通讯作者: Ogata T.