GENETIC ANALYSIS OF HIRSCHSPRUNG DISEASE

先天性巨结肠症的遗传学分析

基本信息

批准号：
7410116
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 44.52万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7410116
关键词：
16q 19q Adult Affect Alleles Base Sequence Binding Biochemical Pathway Biological Assay Biology Candidate Disease Gene Chromosome Mapping Chromosomes, Human, Pair 21 Clinical Code Collection Complex Congenital Abnormality Congenital Megacolon Conserved Sequence Data Databases Descending colon Disease Disease susceptibility Down Syndrome Embryo Endothelin B Receptor Endothelin-3 Endothelin-converting enzyme 1 Family Functional RNA Funding Gastrointestinal tract structure Gender Gene Combinations Gene Mutation Genes Genetic Genetic Screening Genomics Genotype Grant Haplotypes Homeobox Genes Hypercapnic respiratory failure Individual Information Resources Internet Lead Left colic flexure Ligands Literature Location Mennonite Molecular Molecular Genetics Molecular Profiling Mus Mutation Nature Neuroglia Numbers Parents Pathway interactions Patients Penetrance Phenotype Play Predisposition Proteins Range Research Personnel Research Support Resolution Resources Reverse Transcriptase Polymerase Chain Reaction Risk Role Siblings Sigmoid colon Single Nucleotide Polymorphism Son Submucous Plexus Support Groups Susceptibility Gene Symptoms Syndrome Testing Tissue Sample Tissues Transverse colon base comparative embryo tissue ganglion cell gene discovery genetic analysis genetic pedigree human disease mouse model mutant neurotrophic factor neurturin novel proto-oncogene protein c-ret response superoxide dismutase 1 transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Hirschsprung disease (HSCR), or aganglionic megacolon, is a relatively common, multifactorial birth defect associated with the lack of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses in the gastrointestinal tract. Clinically, the symptoms range from mild to severe and involve aganglionosis of the transverse colon and beyond (long segment: L-HSCR), the splenic flexure and the descending colon (short segment: S-HSCR), or the sigmoid colon only (classic HSCR). Research supported by this grant has led to the identification and biology of five genes involved in HSCR susceptibility: the receptor tyrosine kinase RET, RET's ligand glial cell-derived neurotrophic factor (GDNF), the endothelin receptor B (EDNRB), EDNRB's ligand endothelin-3 (EDN3) and the transcription factor SOX10. Others have identified rare mutations in the alternative RET ligand neurturin (NTN), ECE1 (endothelin converting enzyme-1) and the SMAD interacting protein 1 (SMADIP1). In the previous funding period we have demonstrated multigenic inheritance in all forms of HSCR; RET mutations are necessary but not sufficient in all forms of HSCR; the existence of a common non-coding RET mutation; tissue-specific genetic interaction between RET and EDNRB; the location of novel major susceptibility factors; and, a likely interaction between RET and SOD1 (superoxide dismutase 1) as an explanation of HSCR in trisomy 21 patients. We postulate that HSCR is oligogenic, always requiring RET and other interacting disease susceptibility alleles with phenotypic expression depending on the pathways compromised. Proving this hypothesis by identifying the major genes and their specific mutations, and identifying the molecular interactions, forms the basis of this proposal. We focus on using human disease families, mouse models of HSCR gene mutations and functional analyses of mutations to prove our hypotheses. Importantly, sequence-based genomic analysis plays a major role in gene discovery in this project. The long-term objective of this study is to understand the molecular genetic basis of HSCR. More generally, our aim is to develop a paradigm for sequence-based biology in complex, human diseases.

描述（由申请人提供）：Hirschsprung疾病（HSCR）或Aganglionic Megacolon是一种相对常见的，多因素的出生缺陷，与肌动物（Auerbach）和粘膜粘膜粘膜（Meissner）（Meissner）的固有神经节细胞有关。在临床上，症状从轻度到重度，涉及横向结肠及其他（长节：L-HSCR），脾屈曲和降结肠（短节：S-HSCR）或仅sigmoid colon仅（Classic hscr）（经典HSCR）。这项赠款支持的研究导致了涉及HSCR易感性涉及的五个基因的鉴定和生物学：受体酪氨酸激酶RET，RET的RET的配体胶质细胞衍生的神经营养因子（GDNF），内皮蛋白受体B（EDNRB），EDNRB的EDNRB的配体Endothelin-3（EDN3（EDN3）和转录，其他人则发现了替代性RET配体神经蛋白（NTN），ECE1（内皮素转化酶-1）和SMAD相互作用蛋白1（SMADIP1）中的罕见突变。在上一个资金期间，我们在所有形式的HSCR中都证明了多基因遗传。 RET突变是必要的，但在所有形式的HSCR中都不足；存在常见的非编码RET突变； RET和EDNRB之间的组织特异性遗传相互作用；新型主要易感因素的位置；并且，RET和SOD1（超氧化物歧化酶1）之间的可能相互作用可能是对三体疾病患者的HSCR的解释。我们假设HSCR具有寡聚性，始终需要RET和其他相互作用的疾病易感性等位基因，并取决于受损的途径。通过识别主要基因及其特定突变并确定分子相互作用来证明这一假设，这是该提议的基础。我们专注于使用人类疾病家族，HSCR基因突变的小鼠模型以及突变的功能分析以证明我们的假设。重要的是，基于序列的基因组分析在该项目的基因发现中起着重要作用。这项研究的长期目标是了解HSCR的分子遗传基础。更普遍地，我们的目的是为复杂的人类疾病中的基于序列的生物学开发一个范式。