Genetic Analysis of Human Holoprosencephaly

人类前脑无裂畸形的遗传分析

• 批准号: 7051444
• 负责人: JEFFREY E MING
• 金额: $ 37.48万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051444
• 关键词: animal genetic material tag; biological signal transduction; biotechnology; chromosome aberrations; chromosome deletion; clinical research; comparative genomic hybridization; congenital brain disorder; congenital oral /facial /cranial defect; cytogenetics; developmental genetics; disease /disorder etiology; disease /disorder model; family genetics; fluorescent in situ hybridization; gene duplication; gene expression; gene mutation; gene rearrangement; genetic disorder; genetic screening; human genetic material tag; human subject; karyotype; laboratory mouse; microarray technology; molecular genetics

DESCRIPTION (provided by applicant): Molecular genetic studies of congenital craniofacial anomalies have greatly enhanced our understanding of human face and eye development. For example, studies of holoprosencephaly (HPE), a common brain abnormality associated with malformations of the face, eyes, palate, and teeth, have led to the identification of genes required for normal craniofacial development. The anomalies seen in HPE can be severe and include cyclopia, nasal anomalies, and cleft lip/palate. Recently, several genes have been shown to be associated with human HPE. However, most HPE patients still do not have a defined genetic defect. By further exploring the genetic basis of HPE, we seek to gain insight into HPE and the critical genes that regulate craniofacial and brain development. We hypothesize that additional genes and chromosomal regions are associated with human HPE. Since cytogenetically visible chromosomal abnormalities have been noted in a significant proportion of HPE patients, we hypothesize that a subset of HPE cases with a normal karyotype have a submicroscopic chromosomal alteration. We will perform array-based comparative genomic hybridization (aCGH) to identify subtle duplications and deletions. We will characterize the chromosomal rearrangements detected by this method. In addition, since more than 80% of the HPE cases with a normal karyotype in our cohort do not have a mutation in one of the known HPE genes, we will identify additional genes that are associated with human HPE. Based on the array CGH studies, candidate genes will be selected and analyzed. Also, candidate genes will be examined based on their role in signaling pathways implicated in HPE, their function in brain and craniofacial development, and/or their chromosomal location in a region associated with HPE. With these studies, we will further elucidate the genetic etiology of HPE and gain important insight into causes of congenital craniofacial and brain anomalies.

描述（由申请人提供）：先天性颅面异常的分子遗传学研究极大地增强了我们对人脸和眼睛发育的理解。例如，前脑无裂畸形 (HPE) 是一种与面部、眼睛、上颚和牙齿畸形相关的常见大脑异常，对前脑无裂畸形 (HPE) 的研究已经确定了正常颅面发育所需的基因。 HPE 中出现的异常可能很严重，包括独眼、鼻异常和唇裂/腭裂。最近，一些基因已被证明与人类 HPE 相关。然而，大多数 HPE 患者仍然没有明确的遗传缺陷。通过进一步探索 HPE 的遗传基础，我们试图深入了解 HPE 以及调节颅面和大脑发育的关键基因。 我们假设其他基因和染色体区域与人类 HPE 相关。由于在相当大比例的 HPE 患者中发现了细胞遗传学上可见的染色体异常，我们假设具有正常核型的 HPE 病例子集存在亚显微染色体改变。我们将进行基于阵列的比较基因组杂交（aCGH）来识别细微的重复和缺失。我们将描述通过这种方法检测到的染色体重排的特征。此外，由于我们队列中 80% 以上具有正常核型的 HPE 病例在已知的 HPE 基因之一中没有突变，因此我们将鉴定与人类 HPE 相关的其他基因。基于阵列 CGH 研究，将选择并分析候选基因。此外，还将根据候选基因在与 HPE 相关的信号通路中的作用、它们在大脑和颅面发育中的功能和/或它们在与 HPE 相关的区域中的染色体位置进行检查。通过这些研究，我们将进一步阐明 HPE 的遗传病因，并深入了解先天性颅面和大脑异常的原因。