Identifying new genes for branchio-oto-renal syndrome

鉴定鳃耳肾综合征的新基因

• 批准号: 7334202
• 负责人: FRIEDHELM HILDEBRANDT
• 金额: $ 31.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7334202
• 关键词: Affect; Animal Model; Binding; Branchial arch structure; Branchio-Oto-Renal Syndrome; Caenorhabditis elegans; Candidate Disease Gene; Chromosomes; Complex; DNA Binding; DNA-Protein Interaction; Data; Databases; Defect; Development; Disease; Drosophila eye; Ear; Gene Mutation; Genes; Genetic; Genome; Genotype; Hearing; Human; Individual; Kidney; Maps; Mutation; Organogenesis; Orthologous Gene; Patients; Phenotype; Play; Proteins; Regulation; Research Personnel; Role; Syndrome; Testing; Urinary tract; developmental disease; hearing impairment; homeodomain; insight; kindred; malformation; member; positional cloning; programs; protein protein interaction; segregation

DESCRIPTION (provided by applicant): Identification of new genes for branchio-oto-renal syndrome. Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of hearing loss, renal anomalies, and branchial arch defects. Branchio-otic syndrome (BO) is a related disorder without renal anomalies. Dominant mutations in the human ortholog of the Drosophila eyes absent gene (EYA1) cause BOR and BO. By total genome search for linkage in a large kindred of 18 individuals affected with BO, we mapped a new gene locus (BOS3) to chromosome 14q21. Within the 33 Mb critical genetic interval we located the SIX1 gene, which is known to play a role in the PAX-EYA-SIX hierarchy of developmental regulation in the organogenesis of kidney and ear. By direct sequencing we identified 3 different SIX1 mutations in this kindred and in 2 additional kindred with BOR/BO, thus identifying SIX1 as a new gene causing BOR and BO. By functional analysis we show that all 3 mutations interfere with Eya1-Six1 protein-protein interaction, and that the two homeodomain mutations impede Six1-DNA binding. In addition, we generated first evidence that SOX13 mutations may be found in patients with BOR/BO. The C. elegans INTERACTOME project recently confirmed eya-1/six-1 interaction and identified in this model organism many further eya-1 interaction partners, the human orthologs of which represent excellent candidate genes for BOR/BO. This proposal is aimed at the identification of further genes, mutations in which cause BOR/BO and at the functional characterization of SIX1, SOX13, and related genes within the context of BOR/BO and kidney and ear development in humans. Specifically, we propose to: 1) Detect further mutations in the newly identified BOR/BO genes SIX1 and SOX13, and study their functional role for kidney and ear developmental defects in BOR/BO. 2) Identify further genes as responsible for BOR/BO, using as candidate genes members of the Eya1/Six1 transcriptional complex and eya-1 binding partners derived from the C. elegans INTERACTOME data, and study genotype/phenotype relationships. 3) Identify a new gene causing BO by positional cloning in a new large BOR/BO kindred. Identification of new genes causing branchio-oto-renal syndrome will offer new insights into the pathomechanisms of hearing defects, urinary tract malformations as well as kidney and ear development.

描述(由申请者提供)：鉴定鳃-耳-肾综合征的新基因。布兰奇奥-耳-肾综合征(Bor)是一种常染色体显性遗传性发育障碍，其特征是听力损失、肾脏异常和颧弓缺陷。布兰奇奥-奥氏综合征(BO)是一种无肾脏异常的相关疾病。果蝇眼睛缺失基因(EYA1)在人类直系同源基因中的显性突变导致BOR和BO。通过对18个BO家系进行全基因组连锁搜索，我们将一个新的基因座(BOS3)定位在染色体14q21上。在33Mb的关键遗传区间内，我们定位了SIX1基因，该基因在肾脏和耳朵器官发生的PAX-EYA-6级发育调控中发挥作用。通过直接测序，我们在该家系和另外2个BOR/BO家系中发现了3个不同的SIX1突变，从而确定SIX1是一个新的引起BOR和BO的基因。通过功能分析，我们发现这三个突变都干扰了Eya1-SIX1蛋白与蛋白质的相互作用，并且两个同源结构域突变阻碍了SIX1与DNA的结合。 此外，我们还首次提出了在BOR/BO患者中可能发现SOX13突变的证据。线虫互作组计划最近证实了eya-1/Six-1的相互作用，并在这个模式生物中发现了许多进一步的eya-1相互作用伙伴，其人类同源基因代表了Bor/BO的优秀候选基因。 这一建议旨在进一步鉴定导致BOR/BO的基因突变，以及在人类BOR/BO以及肾脏和耳朵发育的背景下SIX1、SOX13和相关基因的功能特征。 具体来说，我们建议： 1)检测新发现的Bor/BO基因SIX1和SOX13的进一步突变，并研究它们在Bor/BO肾脏和耳朵发育缺陷中的功能作用。 2)利用线虫互作组数据中的Eya1/SIX1转录复合体成员和eya-1结合伙伴作为候选基因，进一步确定与Bor/BO相关的基因，并研究基因型/表型之间的关系。 3)在一个新的BOR/BO大家系中进行定位克隆，发现一个引起BO的新基因。新基因的发现将对听力缺陷、尿路畸形以及肾脏和耳朵发育的发病机制提供新的见解。