Molecular Genetics of Holoprosencephaly

前脑无裂畸形的分子遗传学

• 批准号: 18591177
• 负责人: MIYASHITA Toshiyuki
• 金额: $ 2.57万
• 依托单位: Kitasato University (2007)National Research Institute for Child Health and Development (2006)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591177/
• 关键词: Genetics; Holoprosencephaly; Cerebral Development; Polymorphism

Holoprosencephaly (HPE) is a congenital disorder in which the formation of cerebral hemisphere is inhibited to a various degree. We found a patient with middle interhemispheric variant (also called syntelencephaly), a subtype of HPE, carrying a deletion in the long arm of chromosome 6. Using a high-resolution oligonucleotide microarray, we showed that the deletion is about 10 Mb-long including a promoter, exon 1 and exon 2 of the EYA4 gene. This result prompted us to investigate the function of the EYA4 protein.The luciferase assay using a Gli-luciferase reporter revealed that EYA4 promotes sonic hedgehog (SHH) pathway in cooperation with SIX3, a product of one of the HPE responsible genes. Moreover, EYA4 colocalized with SIX3 in the nucleus when tagged proteins were transiently expressed in HeLa cells and these two proteins were coimmunoprecipitated with each other. These results indicate that EYA4 promotes SHH pathway directly or indirectly by associating with SIX3 and, therefore, is one of the candidate genes for HPE.

无前脑畸形(HPE)是一种大脑半球的形成受到不同程度抑制的先天性疾病。我们发现一例HPE的亚型--中脑间变异患者，在6号染色体的长臂上有一个缺失。利用高分辨率的寡核苷酸芯片，我们发现该缺失长约10Mb，包括EYA4基因的一个启动子、外显子1和外显子2。这一结果促使我们对EYA4蛋白的功能进行了研究。使用Gli-荧光素酶报告的荧光素酶分析表明，EYA4与HPE相关基因之一的产物Six3协同促进sonic hedgehog(SHH)途径。此外，当标记蛋白在HeLa细胞中瞬时表达时，EYA4和Six3在细胞核中共存，并且这两种蛋白相互免疫共沉淀。这些结果表明，EYA4通过与Six3结合直接或间接促进SHH途径，是HPE的候选基因之一。

项目成果

A new mutation of the PTCH gene in a patient with nevoid basal cell carcinoma syndrome associated with West syndrome

West综合征相关痣样基底细胞癌综合征患者PTCH基因新突变

• 发表时间: 2007
• 期刊: Pediatr.Neurol 37
• 作者: Tachi;N.
• 通讯作者: N.

Spectrum of mutations in the tumor-suppressor gene, PATCHED-1,in patients with nevoid basal cell carcinoma syndrome

痣样基底细胞癌综合征患者肿瘤抑制基因 PATCHED-1 的突变谱

• 发表时间: 2007
• 期刊: Neuro-oncol 9
• 作者: Miyashita;T.
• 通讯作者: T.

High-density oligonucleotide array with sub-kilobase resolution reveals breakpoint information of submicroscopic deletions in nevoid basal cell carcinoma syndrome

• DOI: 10.1007/s00439-007-0419-y
• 发表时间: 2007-12-01
• 期刊: HUMAN GENETICS
• 影响因子: 5.3
• 作者: Fujii, Katsunori;Ishikawa, Shumpei;Miyashita, Toshiyuki
• 通讯作者: Miyashita, Toshiyuki

U7 snRNA-mediated correction of aberrant splicing caused by activation of cryptic splice sites.

U7 snRNA 介导的对隐藏剪接位点激活引起的异常剪接的纠正。

• 发表时间: 2007
• 期刊: Journal of Human Genetics 52
• 作者: Uchikawa;H.;et. al.
• 通讯作者: et. al.

Pached-1遺伝子と母斑基底細胞癌症候群

Pached-1基因与痣基底细胞癌综合征

• 发表时间: 2007
• 期刊: 家族性腫瘍 7
• 作者: Uchikawa;H.;Shimada A. et al.;宮下 俊之
• 通讯作者: 宮下 俊之