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：
10063826
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063826
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 Genitalia 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 Prognosis 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 overexpression penile hypoplasia 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，先天性泌尿生殖系统（GU）出生缺陷是最常见的出生缺陷。男性，但对其病因知之甚少，这在一定程度上反映了当前的临床情况。观点认为，由于大多数出生缺陷都可以通过手术修复，因此没有什么因此，相关研究相对较少。然而，直到最近我们的研究表明，看似简单的出生缺陷，例如尿道下裂或隐睾，可能与其他更明显的未被重视的疾病有关缺陷，例如影响肾脏、心脏、眼睛或行为的缺陷。 GU 个体中的微缺失和微重复（称为拷贝数变异，CNV）使我们能够检验 CNV 编码基因的基因剂量变化这一假设区域是泌尿生殖发育的重要调节器，当单倍体不足或重复的正常泌尿生殖发育受到影响，导致上颌出生缺陷我们成功地使用此策略识别了 15 种不同的泌尿生殖道。以前未被识别的基因，当微复制或微删除时会导致某些情况例如隐睾、尿道下裂、性模糊（性别分化障碍- DSD）、肾脏和泌尿道先天性异常（CAKUT）以及严重分娩诸如膀胱外翻性尿道上裂复合体（BEEC）等缺陷的因果关系已得到证实。通过识别所涉及的机制并通过重演出生缺陷值得注意的是，单倍剂量不足或过度表达的动物模型。变化影响了新颖的主要信号传导途径和翻译后修饰，在这个提案中，我们重点关注定义两种机制。我们将测试阴茎异常患者中常见的候选基因。假设 22q13.3 处的 RBFOX2 CNV 通过产生替代品而导致 GU 异常 FGFR2 的剪接变体（FGFR2IIIc 而不是 FGFR2IIIb）阻碍阴茎生长和尿道第二个假设是 Kank1 在 9p24.3 处的缺失会削弱 β-连环蛋白。生殖器结节发育过程中 FGF8 表达的调节导致阴茎异常。这些研究不仅将确定先前未识别的 GU 异常原因，而且还将确定另外，这些基因剂量变化的相关后遗症在未来，这样的知识。可能会改进诊断和治疗方法，以改善这些常见的分娩情况缺陷。

项目成果

期刊论文数量（46）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

INSL3/RXFP2 signaling in testicular descent.

睾丸下降中的 INSL3/RXFP2 信号传导。

DOI：
发表时间：
2009-04
期刊：
影响因子：
5.2
作者：
Feng, Shu;Ferlin, Alberto;Truong, Anne;Bathgate, Ross;Wade, John D;Corbett, Sean;Han, Shuo;Tannour;Lamb, Dolores J;Foresta, Carlo;Agoulnik, Alexander I
通讯作者：
Agoulnik, Alexander I

The use of fluorescent in situ hybridization in male infertility.

荧光原位杂交在男性不育症中的应用。

DOI：
发表时间：
2010-08
期刊：
影响因子：
0
作者：
Hwang, Kathleen;Weedin, John W;Lamb, Dolores J
通讯作者：
Lamb, Dolores J

Are worldwide sperm counts declining?

全球精子数量正在下降吗？

DOI：
发表时间：
2021-12
期刊：
影响因子：
6.7
作者：
Jørgensen, Niels;Lamb, Dolores J;Levine, Hagai;Pastuszak, Alexander W;Sigalos, John T;Swan, Shanna H;Eisenberg, Michael L
通讯作者：
Eisenberg, Michael L

DYRK1A 相关智力障碍：一种与肾脏和泌尿道先天性异常相关的综合征。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Blackburn, Alexandria T M;Bekheirnia, Nasim;Uma, Vanessa C;Corkins, Mark E;Xu, Yuxiao;Rosenfeld, Jill A;Bainbridge, Matthew N;Yang, Yaping;Liu, Pengfei;Madan;Delgado, Mauricio R;Hudgins, Louanne;Krantz, Ian;Rodriguez
通讯作者：
Rodriguez

Murine model indicates 22q11.2 signaling adaptor CRKL is a dosage-sensitive regulator of genitourinary development.

小鼠模型表明 22q11.2 信号适配器 CRKL 是泌尿生殖发育的剂量敏感调节剂。