Identifying new genes for branchio-oto-renal syndrome

鉴定鳃耳肾综合征的新基因

• 批准号: 7160533
• 负责人: FRIEDHELM HILDEBRANDT
• 金额: $ 32.19万
• 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/7160533
• 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（由申请人提供）：支耳肾综合征新基因的鉴定。鳃裂-耳-肾综合征（BOR）是一种常染色体显性发育障碍，以听力损失、肾脏异常和鳃裂弓缺陷为特征。鳃裂综合征（BO）是一种无肾脏异常的相关疾病。果蝇眼缺失基因（EYA1）在人类同源基因上的显性突变导致BOR和BO。通过对一个有18名BO患者的大亲缘系进行全基因组连锁搜索，我们将一个新的基因位点BOS3定位在染色体14q21上。在33 Mb的关键遗传间隔内，我们找到了SIX1基因，该基因已知在肾脏和耳朵器官发生的PAX-EYA-SIX发育调控中发挥作用。通过直接测序，我们在该亲缘系和另外2个BOR/BO亲缘系中发现了3个不同的SIX1突变，从而确定SIX1是导致BOR和BO的新基因。通过功能分析，我们发现这3个突变都干扰了Eya1-Six1蛋白与蛋白的相互作用，并且这两个同源结构域突变阻碍了Six1-DNA的结合。