Single gene pathogenic variants associated with BEEC (Bladder Exstrophy, Epispadias, Complex)

与 BEEC（膀胱外翻、尿道上裂、复合体）相关的单基因致病变异

• 批准号: 10357856
• 负责人: Angie Child Jelin
• 金额: $ 19.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357856
• 关键词: Address; Affect; Anatomy; Bladder; Bladder Exstrophy; CRISPR/Cas technology; Candidate Disease Gene; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Congenital omphalocele; Databases; Defect; Development; Development Plans; Developmental Biology; Discipline of obstetrics; Embryo; Epispadias; Etiology; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genitourinary system; Genome; Genomics; Genotype; Goals; Gynecology; Impairment; Imperforate Anus; Individual; Intestines; Knockout Mice; Magnetic Resonance Imaging; Medical; Mentors; Mentorship; Methods; Molecular; Monozygotic twins; Morbidity - disease rate; Mosaicism; Mus; Mutation; Oocytes; Operative Surgical Procedures; Parents; Pathogenicity; Pathologist; Pathway interactions; Patients; Phenotype; Positioning Attribute; Prenatal Diagnosis; Rare Diseases; Research Personnel; Severities; Sexual Dysfunction; Signal Pathway; Source; Spinal; Structural defect; Technology; Testing; The Jackson Laboratory; Therapeutic; Training; Urinary tract; Urinary tract infection; Validation; Variant; WNT3 gene; Work; base; biobank; body system; career development; causal variant; contrast enhanced; de novo mutation; exome sequencing; experience; fetal; genetic variant; genome sequencing; loss of function; medical schools; medical specialties; mortality; mouse model; new technology; prenatal; proband; professor; rare condition; reconstruction; reproductive fitness; stem; targeted treatment; urologic; whole genome

PROJECT SUMMARY This K23 application is submitted by Angie C. Jelin, MD, Assistant Professor of Gynecology and Obstetrics/Genetics at the Johns Hopkins School of Medicine. Dr. Jelin’s long term goal is to become an independent investigator in fetal urinary tract anomalies. Towards this goal, she proposes a mentored career development plan that provides training in whole genome sequencing (WGS), genomics, CRISPR/Cas9, and mouse phenotyping. Urogenital anomalies account for 20-30% of prenatally detected structural defects. Bladder Exstrophy Epispadias Complex (BEEC) describes a subset of anomalies with a spectrum of developmental defects ranging from a mild form of epispadias, to classic bladder exstrophy, to omphalocele, exstrophy, imperforate anus, spinal anomalies (OEIS) complex. Patients with BEEC suffer substantial morbidity and mortality due to impaired genito-urinary dysfunction. The etiology of BEEC is largely unknown. Elucidating the underlying genetic component is critical to gaining a better understanding of the developmental signaling pathways and is likely the first step to developing targeted therapy. Variants in genes identified in other urogenital anomalies appear to be responsible for some cases of BEEC including IS, WNT3, WNT9b, PLAG1 and p63. We propose to take advantage of our extensive analytical experience in the Baylor Hopkins Center for Mendelian Genomics and perform WGS on parent-proband trios for whom the proband has BEEC. One study utilizing whole exome sequencing (WES), identified candidate genes (SLC20A1 and CELSR3) in 2 out of 8 affected patients, providing reassurance that our proposed strategy will be successful. Following WGS, we will explore the pathogenicity of genetic variants by employing a knockout mouse model using CRISPR/Cas9 technology via collaboration with the Jackson Laboratory. Final validation will include mouse phenotyping by dynamic contrast-enhanced MRI under the expertise of, Cory Brayton, mouse pathologist. Aim 1. To identify the genetic basis of BEEC through Whole Genome Sequencing (WGS) Aim 2a. To create the founder (F0) homozygous knockout mouse using CRISPR/Cas9. Aim 2b. To define the murine model phenotype using dynamic contrast enhanced MRI.

项目摘要 K23申请由Angie C提交。Jelin，医学博士，妇科助理教授， 约翰霍普金斯医学院的产科/遗传学。Jelin博士的长期目标是 成为胎儿泌尿道异常的独立调查员。为了实现这一目标，她 提出了一个指导性的职业发展计划，提供全基因组方面的培训， 测序（WGS）、基因组学、CRISPR/Cas9和小鼠表型。 泌尿生殖系统异常占产前检测到的结构缺陷的20-30%。膀胱 外翻性尿道上裂综合征（BEEC）描述了一组异常， 从轻度尿道上裂到典型的膀胱外翻， 脐膨出、外翻、无肛、脊柱异常（OEIS）综合征。患者 BEEC由于受损的生殖泌尿功能障碍而遭受大量的发病率和死亡率。的 BEEC的病因在很大程度上是未知的。阐明潜在的遗传成分对于 更好地了解发育信号通路，可能是第一个 发展靶向治疗的一步。在其他泌尿生殖系统异常中发现的基因变异 似乎与一些BEEC病例有关，包括IS、WNT 3、WNT 9 b、PLAG 1和 第63页。我们建议利用我们在贝勒大学的丰富分析经验 霍普金斯孟德尔基因组学中心，并对父母先证者三人组进行WGS， 先证者患有BEEC。一项利用全外显子组测序（WES）的研究发现， 候选基因（SLC 20 A1和CELSR 3）在8名受影响的患者中有2名， 我们提出的策略会成功在WGS之后，我们将探索致病性 通过使用CRISPR/Cas9技术的基因敲除小鼠模型， 与杰克逊实验室合作。最终验证将包括小鼠表型分析， 在小鼠病理学家Cory Brayton的专业知识下进行动态对比增强MRI。 目标1。通过全基因组测序（WGS）确定BEEC的遗传基础 目标2a。使用CRISPR/Cas9创建创始者（F0）纯合敲除小鼠。 目标2b。使用动态对比增强MRI确定小鼠模型表型。