Screening copy number variations by array comparative genomic hybridization in 30 patients with congenital hypopituitarism.

通过阵列比较基因组杂交筛选 30 例先天性垂体功能减退症患者的拷贝数变异。

• 批准号: 22790999
• 负责人: TAKAGI Masaki
• 金额: $ 1.91万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22790999/
• 关键词: 先天性下垂体機能低下症; copy number variations; コピーナンバーバリエーション; 小児科学; 下垂体機能低下症

Objective : Mutations in transcription factors genes, which are regulated spatially and temporally in the pituitary gland, result in congenital hypopituitarism(CH) in humans. The prevalence of CH attributable to known transcription factor mutations appears to be rare and other causative genes for CH would remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its etiology, especially in syndromic CH.Subjects and Methods : We enrolled 88(Syndromic : 30, Non-syndromic 58) Japanese CH patients. We performed an array CGH screen of 30 syndromic CH patients to determine the role of copy number variations(CNVs) in the etiology of the disease.Results : We identified one heterozygous 350kb deletion of PAX6 enhancer region in one patient showing isolated GH deficiency, cleft palate, and optic disc cupping. For all patients, we analyzed all coding exons and flanking introns ofPAX6 and identified a novel mutation, namely p. N116S in one non-syndromic CH patient showing isolated GH deficiency. In vitro experiments showed that N116S PAX6 mutation was associated with an impairment of the transactivation capacities of PAX6 binding element, without any dominant-negative effects.Conclusions : PAX6 is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. This study showed, for the first time, that heterozygous PAX6 mutations are associated with CH patients with or without ocular malformation.

目的：转录因子基因的突变在垂体中受到空间和时间的调节，导致人类先天性垂体功能减退症（CH）。由已知转录因子突变引起的CH的患病率似乎很罕见，CH的其他致病基因仍有待鉴定。由于CH的零星发生，从头染色体重排是可以想象的参与其病因的分子机制之一，特别是在综合征CH。主题和方法：我们招募了88（综合征：30，非综合征58）日本CH患者。我们进行了一个阵列CGH屏幕的30综合征CH患者，以确定拷贝数变异（CNVs）的作用，在病因的diseases.Results：我们确定了一个杂合350 kb的PAX6增强子区域缺失的患者表现出孤立的GH缺乏症，腭裂，视盘杯状。对于所有患者，我们分析了PAX6的所有编码外显子和侧翼内含子，并确定了一个新的突变，即p.N116S在一个非综合征CH患者显示孤立的GH缺乏症。体外实验表明，N116 S PAX6突变与PAX6结合元件的反式激活能力的损害，没有任何显性负效应。结论：PAX6是一个众所周知的调节器的眼睛发育，其杂合突变导致先天性眼畸形，如无虹膜。这项研究首次表明，杂合PAX6突变与有或无眼部畸形的CH患者相关。

项目成果

本邦におけるヒト先天性下垂体機能低下症の包括的遺伝子解析

日本人类先天性垂体功能低下症综合遗传分析

• 发表时间: 2010
• 作者: 高木優樹;石井智弘;井ノ口美香子;天野直子;室谷浩二;朝倉由美;安達昌功;長谷川奉延
• 通讯作者: 長谷川奉延

PAX6は先天性下垂体機能低下症の責任遺伝子である

PAX6是导致先天性垂体功能减退症的基因

• 发表时间: 2012
• 作者: 高木優樹;長崎啓祐;石井智弘;内田登;天野直子;三井俊賢;室谷浩二;朝倉由美;安達昌功;長谷川奉延
• 通讯作者: 長谷川奉延

Heterozygous C-propeptide mutations in COL1A1 : osteogenesis imperfect a type IIC and dense bone variant

COL1A1 杂合 C 前肽突变：成骨不完善 a 型 IIC 和致密骨变异

• DOI: 10.1002/ajmg.a.34152
• 发表时间: 2011
• 期刊: Am J Med Genet A
• 影响因子: 2
• 作者: Takagi M;Hori N;Chinen Y;Kurosawa K;Tanaka Y;Oku K;Sakata H;Fukuzawa R;Nishimura G;Spranger J;Hasegawa T
• 通讯作者: Hasegawa T