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：
7189913
负责人：
ARAVINDA CHAKRAVARTI
金额：
$ 44.11万
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/7189913
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）：先天性巨结肠（HSCR）或无神经节巨结肠是一种相对常见的多因素出生缺陷，与胃肠道肌间神经丛（Auerbach）和粘膜下神经丛（Meissner）缺乏固有神经节细胞有关。临床上，症状从轻微到严重不等，涉及横结肠及以上（长段：L-HSCR）、脾曲和降结肠（短段：S-HSCR）或仅乙状结肠（经典高速SCR）。此项资助支持的研究已对与 HSCR 易感性相关的 5 个基因进行了鉴定和生物学研究：受体酪氨酸激酶 RET、RET 的配体胶质细胞源性神经营养因子 (GDNF)、内皮素受体 B (EDNRB)、EDNRB 的配体内皮素。 3 (EDN3) 和转录因子 SOX10。其他人已经发现了替代 RET 配体神经营养因子 (NTN)、ECE1（内皮素转换酶-1）和 SMAD 相互作用蛋白 1 (SMADIP1) 的罕见突变。在之前的资助期间，我们已经证明了所有形式的 HSCR 中的多基因遗传； RET 突变对于所有形式的 HSCR 来说都是必要的，但还不够；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；新的主要易感因素的位置；并且，RET 和 SOD1（超氧化物歧化酶 1）之间可能存在相互作用，作为 21 三体患者中 HSCR 的解释。我们假设 HSCR 是寡基因的，总是需要 RET 和其他相互作用的疾病易感性等位基因，其表型表达取决于受损的途径。通过识别主要基因及其特定突变并识别分子相互作用来证明这一假设，构成了该提案的基础。我们专注于使用人类疾病家族、HSCR 基因突变的小鼠模型和突变的功能分析来证明我们的假设。重要的是，基于序列的基因组分析在该项目的基因发现中发挥着重要作用。本研究的长期目标是了解 HSCR 的分子遗传学基础。更一般地说，我们的目标是开发复杂人类疾病中基于序列的生物学范例。