Genetic Basis of Birth Defects in 22q11 Deletion Syndrome

22q11 缺失综合征出生缺陷的遗传基础

• 批准号: 7813774
• 负责人: BERNICE E MORROW
• 金额: $ 24.65万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7813774
• 关键词: 22q11 Deletion Syndrome; 22q11.2; Alleles; Animal Model; Base Pairing; Behavior Disorders; Biological; Birth; CRKL gene; Candidate Disease Gene; Cardiovascular system; Characteristics; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 16; Clinical; Congenital Abnormality; DNA Sequence Rearrangement; Defect; Development; Developmental Delay Disorders; DiGeorge Syndrome; Disease; Distal; Engineering; Evolution; Exposure to; Face; Fetal Alcohol Exposure; Future; Genes; Genetic; Genomics; Genotype; Goals; Human; Human Chromosomes; Immune; Individual; Live Birth; Maps; Mild mental retardation; Modeling; Molecular; Mus; Neurocognitive; Neurocognitive Deficit; Neurologic; Organizational Change; Outcome; Pathogenesis; Patients; Penetrance; Pharmaceutical Preparations; Phenocopy; Phenotype; Pregnancy; Primates; Severities; Shprintzen syndrome; Site; Syndrome; Synteny; System; Teratogens; Testing; Tretinoin; Variant; Vitamin A; base; craniofacial; gene function; gene interaction; insight; interest; malformation; microdeletion; mouse model; programs; public health relevance

DESCRIPTION (provided by applicant): Mouse genomic engineering for 22q11.2 rearrangement disorders The 22q11.2 deletion syndrome (22q11DS), also known as velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS), is one of the most common microdeletion disorders in humans, occurring in 1/4,000 live births. Over 90% of patients have a typical 3 Mb (million base pair) deletion, while some have smaller deletions within. The characteristic clinical features include cardiovascular defects, immune, and craniofacial anomalies as well as psychiatric illness and mild mental retardation. Although a handful of candidate genes have been identified and pursued on their own, there is significant evidence that additional genes contribute to the overall phenotype. For example, a gene in the proximal (centromeric) half of the 3 Mb region, termed TBX1, and distal half, termed CRKL have been found to genetically interact for cardiovascular development. Recently, it was found that non-overlapping deletions within the 3 Mb region have been identified in association with the syndrome, suggesting that haploinsufficiency of different genes can contribute to related congenital malformations. Several genes in the proximal 1.5 Mb region are candidates for neurocognitive deficits, but genes in the distal half have not been pursued as of yet. Finally, the disorder occurs with variable expressivity, possibly due to sequence variation in genes on the remaining allele. Understanding gene functions and interactions would provide insights into the molecular pathogenesis of VCFS/DGS. Our hypothesis is that haploinsufficiency of contiguous gene(s) within the 22q11.2 region is responsible for the overall phenotype of the disorder. The genes on 22q11.2 are conserved on mouse chromosome 16. A 1.5 Mb deletion comprising the proximal half of the 22q11.2 region was generated and characterized, but a deletion that is equivalent to the 3 Mb deletion was not made, largely due to past ambiguities in the mouse gene map. In Specific Aim 1, we will use the Cre/loxP system (MICER) to create a deletion that includes most of the genes hemizygous in humans with the typical 3 Mb deletion. These mice should recapitulate the human condition. In Specific Aim 2, we will compare the phenotypes between mice with the 1.5 Mb deletion that was previously generated, Tbx1 and Crkl mice. The studies in Aim 2 will directly test our hypothesis. The next goal would be to perform genotype phenotype correlations by creation of additional alleles with overlapping smaller deletions and duplications and this will be done in the future. We are also interested in modeling the reciprocal 3 Mb duplication syndrome, dup(22)(q11.2, q11.2) and the mice with the duplication can serve this purpose. PUBLIC HEALTH RELEVANCE: We propose to generate a mouse model of velo-cardio-facial/DiGeorge syndrome to test the hypothesis that it results from haploinsufficiency of contiguous genes on 22q11.2.

描述（由申请人提供）：22q11.2重排疾病的小鼠基因组工程22q11.2缺失综合征（22 q11 DS），也称为腭心面综合征/DiGeorge综合征（VCFS/DGS），是人类最常见的微缺失疾病之一，发生率为1/4，000活产婴儿。超过90%的患者具有典型的3 Mb（百万碱基对）缺失，而一些患者具有较小的缺失。典型的临床特征包括心血管缺陷、免疫和颅面异常以及精神疾病和轻度智力迟钝。虽然少数候选基因已被确定和追求自己的，有重要的证据表明，其他基因有助于整体表型。例如，已发现在3 Mb区域的近端（着丝粒）一半（称为TBX 1）和远端一半（称为CRKL）中的基因在心血管发育中遗传相互作用。最近，发现3 Mb区域内的非重叠缺失与该综合征相关，表明不同基因的单倍不足可能导致相关的先天性畸形。近端1.5 Mb区域中的几个基因是神经认知缺陷的候选者，但远端一半的基因尚未被追踪。最后，这种疾病的发生具有可变的表达性，可能是由于剩余等位基因上的基因序列变异。了解基因功能和相互作用将提供深入了解VCFS/DGS的分子发病机制。我们的假设是，22q11.2区域内的连续基因的单倍不足是负责的疾病的整体表型。22q11.2上的基因在小鼠16号染色体上是保守的。产生并表征了包含22q11.2区域的近端一半的1.5Mb缺失，但是没有产生等同于3 Mb缺失的缺失，这主要是由于小鼠基因图谱中过去的模糊性。在特定目标1中，我们将使用Cre/loxP系统（MICER）创建一个缺失，该缺失包括人类中具有典型3 Mb缺失的大多数半合子基因。这些老鼠应该能重现人类的状况。在特定目标2中，我们将比较先前产生的1.5 Mb缺失小鼠Tbx 1和Crkl小鼠之间的表型。目标2中的研究将直接检验我们的假设。下一个目标将是通过创建具有重叠的较小缺失和重复的额外等位基因来进行基因型表型相关性，这将在未来完成。我们也有兴趣建立相互3 Mb重复综合征dup（22）（q11.2，q11.2）的模型，具有重复的小鼠可用于此目的。 公共卫生关系：我们建议生成一个小鼠模型的velo-cardio-facial/DiGeorge综合征，以测试的假设，它的结果从22q11.2上的连续基因的单倍不足。