Improving the Diagnosis of Congenital Genitourinary Birth Defects

改进先天性泌尿生殖出生缺陷的诊断

基本信息

批准号：
9897527
负责人：
Dolores Jean Lamb
金额：
$ 38.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9897527
关键词：
22q13.3 9p24 Actins Affect Alternative Splicing Animal Model Ankyrin Repeat Behavior Benign Binding Birth Bladder Exstrophy Candidate Disease Gene Caring Cell Line Cell Proliferation Cell model Child Childhood Chromosomal Rearrangement Chromosomes Clinical Complex Congenital Abnormality Congenital Disorders Copy Number Polymorphism Cryptorchidism Defect Detection Development Developmental Delay Disorders Diagnosis Disease Elements Embryonic Development Epispadias Etiology Event Eye FGF8 gene FGFR2 gene Family Foxes Funding Future Gametogenesis Gene Dosage Gene Expression Genes Genetic Genetic Counseling Genital system Genitourinary system Genomics Goals Growth Heart Homeostasis Homologous Gene Human Hypospadias In Vitro Individual Intervention Karyotype Kidney Knowledge Lead Medical Medical Genetics Mental Retardation Mesenchymal Molecular Neonatal Operative Surgical Procedures Parents Pathogenicity Patient Care Patients Penile Diseases Physicians Population Post-Translational Protein Processing Pregnancy Preimplantation Diagnosis Protein Isoforms Proteins RNA Splicing RNA-Binding Proteins Recurrence Regulation Research Risk Estimate Series Sex Differentiation Disorders Signal Pathway Signal Transduction Structural Congenital Anomalies Syndrome Technology Testing Therapeutic Tissue-Specific Splicing Tissues Tube Urethra Urinary tract Urologist Variant ambiguous genitalia base beta catenin comparative genomic hybridization congenital anomaly dosage experimental study gene therapy homologous recombination improved in vivo male microdeletion migration mouse model novel outcome forecast overexpression penis polymerization prevent psychologic psychosocial renal agenesis repaired social urinary urogenital tract

项目摘要

Collectively, congenital genitourinary (GU) birth defects are the most common birth defects in males, yet relatively little is known about their cause. In part, this reflects the current clinical perspective that, because most of these birth defects can be surgically repaired, there is nothing to be gained by understanding the cause. Accordingly, relatively little research has been performed until recently. Yet our studies suggest that seemingly simple birth defects like hypospadias or cryptorchidism, may be associated with other more significant underappreciated defects, such as those affecting the kidney, heart, eyes or behavior. Studies of chromosome microdeletions and microduplications (called copy number variations, CNVs) in GU individuals enabled us to test the hypothesis that gene-dosage changes in gene(s) encoded in CNV regions are important regulators of genitourinary development and when haploinsufficient or duplicated normal genitourinary development is impacted causing birth defects of the upper and/or lower genitourinary tract. We successfully used this strategy to identify 15 different previously unrecognized genes that when microduplicated or microdeleted result in conditions such as cryptorchidism, hypospadias, sexual ambiguity (disorders of sexual differentiation- DSD), congenital anomalies of the kidney and urinary track (CAKUT), as well as severe birth defects such as bladder exstrophy epispadias complex (BEEC). Causation was demonstrated through identification of the mechanisms involved and through re-capitulation of the birth defect with animal models of haploinsufficiency or over-expression. Remarkably, gene-dosage changes affected major signaling pathways and post-translational modifications in novel, previously unrecognized ways. In this proposal, we focus on defining the mechanisms of two candidate genes commonly microdeleted in patients with penile anomalies. We will test the hypothesis that RBFOX2 CNVs at 22q13.3 contribute to GU anomalies by producing alternate splice variants of FGFR2 (FGFR2IIIc instead of FGFR2IIIb) hindering penile growth and urethral development. The second hypothesis is that Kank1 deletion at 9p24.3 blunts β-catenin regulation of FGF8 expression during genital tubercle development causing penile anomalies. These studies will not only identify previously unrecognized causes of GU anomalies but also additional, associated sequelae of these gene dosage changes. In the future, such knowledge may lead to improved diagnosis and therapeutic approaches to ameliorate these common birth defects.

总的来说，先天性泌尿生殖器（GU）出生缺陷是最常见的先天缺陷男性对自己的原因知之甚少。部分反映了当前的临床观点是，由于这些出生缺陷大多数可以通过外科手术修复，所以什么都没有要通过理解原因而获得。彼此之间，相对较少的研究是直到最近才能执行。然而，我们的研究表明，看起来很简单的出生缺陷催生或隐性化胆道可能与其他更重要的不被低估有关缺陷，例如影响肾脏，心脏，眼睛或行为的缺陷。染色体的研究 GU个体中的微缺失和微型设备（称为拷贝数变化，CNV）使我们能够检验以下假设：CNV中编码的基因的基因剂量变化区域是泌尿生殖器发展的重要调节因素，以及一单元弥补或重复的正常泌尿生殖器发育受到影响，导致上部出生缺陷和/或较低的生殖道。我们成功地使用了这种策略来识别15种不同的先前未识别的基因，当微重复或微骨骼在条件下会导致例如隐性主义，催生，性歧义（性别差异的疾病） DSD），肾脏和尿路的先天异常（Cakut）以及严重的出生膀胱外膜膜复合体（BEEC）等缺陷。证明了因果关系通过识别所涉及的机制并通过重新识别出生缺陷具有单倍弥补或过表达的动物模型。值得注意的是，基因剂变化影响了新颖的主要信号通路和翻译后修饰，以前无法认可的方式。在此提案中，我们专注于定义两个的机制候选基因通常在阴茎异常患者中被微浸泡。我们将测试假设RBFOX2 CNV在22q13.3通过产生替代方案有助于GU异常 FGFR2（FGFR2IIIC而不是FGFR2IIIB）的剪接变体阻碍阴茎生长和尿道发展。第二个假设是kank1删除为9p24.3钝β-catenin 在生殖结节发育过程中FGF8表达的调节导致阴茎异常。这些研究不仅会识别以前无法识别的GU异常原因，而且还将确定这些基因剂量变化的其他相关后遗症。将来，这种知识可能会改善诊断和治疗方法，以改善这些常见的出生缺陷。