Analysis of LHX gene on human development

LHX基因对人类发育的影响分析

• 批准号: 13470343
• 负责人: ISHIKAWA Mutsuo
• 金额: $ 8.9万
• 依托单位: Asahikawa Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470343/
• 关键词: LHX; Development; Homeobox gene; Mbx; SYCP3; Azoospermia; LIM; 流産; 奇形; ホメオボックス; 小眼症; 遺伝子発現; 発生; 悪性腫瘍

BACKGROUND : Many cases of male infertility are diagnosed as idiopathic, reflecting poor understanding of the molecular defects underlying the abnormality. As more gene mutations causing male infertility in mice become known, there are improving prospects that knowledge about the genetic aetiology of human male infertility can be expanded. Sycp3 encodes a component of the synaptonemal complex A null mutation of Sycp3 in mice causes azoospermia with meiotic arrest. We tested the hypothesis that mutation of the human testis-specific SYCP3 is associated with human non-obstructive azoospermia.METHODS : Human SYCP3 was isolated on the basis of homology between mouse Sycp3 cDNA and human genome sequences at the aminoacid level. Tissue-specific expression of SYCP3 was analysed by PCR of human cDNA. Samples of DNA from 19 azoospermic patients with maturation arrest and 75 normal fertile control men were screened for mutations in the SYCP3 gene by sequence analysis of the gene. The functional significance of the mutations found was analysed by a protein interaction study of the wild-type and truncated SYCP3 proteins.FINDINGS : We identified in two patients a 1 bp deletion (643delA) that results in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the SYCP3 protein. The mutant protein showed greatly reduced interaction with the wild-type protein in vitro and interfered with SYCP3 fibre formation in cultured cells.INTERPRETATION : We suggest that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein via dominant negative interference.

背景技术背景：许多男性不育症被诊断为特发性，反映了对异常背后的分子缺陷的理解不足。随着越来越多的基因突变导致小鼠雄性不育症成为已知的，有改善的前景，有关人类男性不育症的遗传病因学的知识可以扩大。Sycp 3编码联会复合体的一个成分Sycp 3在小鼠中的无效突变导致减数分裂停滞的无精子症。我们测试的假设，人类睾丸特异性SYCP 3的突变与人类非梗阻性无精子症。方法：人类SYCP 3的分离的基础上，小鼠Sycp 3的cDNA和人类基因组序列的同源性在氨基酸水平上。SYCP 3的组织特异性表达通过人cDNA的PCR分析。通过对SYCP 3基因进行序列分析，对19例成熟停滞的无精子症患者和75例正常生育对照男性的DNA样本进行SYCP 3基因突变筛查。发现的突变的功能意义进行了分析的野生型和截短SYCP 3 proteins.FINDINGS的蛋白质相互作用的研究：我们确定在两个病人的1 bp缺失（643 delA），导致在一个过早的终止密码子和截短的C-末端，卷曲螺旋形成区域的SYCP 3蛋白。突变体蛋白表现出大大减少与野生型蛋白质在体外的相互作用，并干扰SYCP 3纤维形成在cultured cells.Interpretation：我们认为，SYCP 3在人类精子发生中具有重要的减数分裂功能，是通过显性负干扰的突变体蛋白质妥协。

项目成果

J Kamimura: "Identification of eight novel NSD1 mutations in Sotos syndrome"J Med Genet. 40・11. c126 (2003)

J Kamimura：“索托斯综合征中八种新的 NSD1 突变的鉴定”J Med Genet 40·11（2003）。

Toshinobu Miyamoto: "Mbx, a novel mouse homeobox gene."Dev Genes Evol. 212・2. 104-106 (2002)

Toshinobu Miyamoto：“Mbx，一种新型小鼠同源框基因。”Dev Genes Evol. 212・2（2002）。

Toshinobu Miyamoto et al.: "Isolation and Expression analysis of the human testis-specific gene, SPERGEN-1, a Spermatogenic Cell-Specific Gene-1."J Assist Reprod Genet. 20・2. 101-104 (2003)

Toshinobu Miyamoto 等人：“人类睾丸特异性基因 SPERGEN-1（生精细胞特异性基因 1）的分离和表达分析”J Assist Reprod Genet 20・2（2003）。

Toshinobu Miyamoto et al.: "Isolation and expression analysis of the testis-specific gene, STRA8, stimulated by retinoic acid gene 8."J Assist Reprod Genet. 19・11. 531-535 (2002)

Toshinobu Miyamoto 等：“视黄酸基因 8 刺激的睾丸特异性基因 STRA8 的分离和表达分析”J Assist Reprod Genet. 19・11 (2002)。

Toshinobu Miyamoto: "Isolation and expression analysis of the testis-specific gene, STRA8, stimulated by retinoic acid gene 8"J Assist Reprod Genet. 19・11. 531-535 (2002)

Toshinobu Miyamoto：“视黄酸基因 8 刺激的睾丸特异性基因 STRA8 的分离和表达分析”J Assist Reprod Genet 19・11 (2002)。