MOLECULAR GENETICS OF NAIL PATELLA SYNDROME

指甲髌骨综合征的分子遗传学

• 批准号: 6375059
• 负责人: IAIN R MCINTOSH
• 金额: $ 34.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375059
• 关键词: alleles; artificial chromosomes; clinical research; congenital skeletal disorder; cytogenetics; denaturing gradient gel electrophoresis; developmental genetics; family genetics; fluorescent in situ hybridization; gene expression; gene rearrangement; genetic library; genetic mapping; genetic markers; genetically modified animals; human subject; laboratory mouse; northern blottings; nucleic acid probes; phenotype; point mutation; polymerase chain reaction; sequence tagged sites; single strand conformation polymorphism; southern blotting

Nail Patella Syndrome (NPS) is a diverse phenotype inherited in an autosomal dominant manner. The syndrome is characterized by dysplasia of the nails, patellae and elbows, as well as open angle glaucoma and potentially lethal nephropathy. It has been established that NPS is the result of heterozygous loss-of- function mutations in the LIM-homeodomain transcription factor, LMX1B. The NPS mutations identified to date are concentrated within the LIM and homeodomains; none have been found within the carboxy-terminal third of the coding region. Comparison with animal models suggests that the orthopaedic problems associated with NPS result from a failure of dorsalization during limb development. The NPS phenotype can vary markedly within families, as well as between unrelated persons. There is no correlation between the severity of the phenotype and LMX1B mutations. The basis for this variation must originate outside the LIM1B coding sequence. Promoter elements controlling LMX1B expression and molecules that interact with LMX1B will be identified. These sequences will be assessed for variants in NPS families exhibiting a range of phenotypic severity. It will also be determined if the carboxy-terminal domain plays a role in the development of the limbs. Interacting proteins will be identified and transgenic mice lacking this domain will be analyzed. This information may allow an accurate prognosis of NPS severity. Not only will these experiments address the question of phenotypic variation within a single gene disorder, but an understanding of how genes interact in the development of a phenotype will help in deriving the etiology of genetically complex conditions. Furthermore, by identification of elements controlling LMX1B expression and the factors interacting with LMX1B, a better model of limb development will be derived.

指甲-髌骨综合征（Nail Patella Syndrome，简称NPH）是一种常染色体显性遗传的疾病。 该综合征的特征是指甲、髌骨和肘部发育不良，以及开角型青光眼和潜在的致命性肾病。 已经确定，LIM是LIM同源结构域转录因子LMX 1B的杂合功能丧失突变的结果。 到目前为止，已发现的LIM突变集中在LIM和同源结构域内;在编码区的羧基末端三分之一内没有发现。 与动物模型的比较表明，矫形问题与脊髓背侧化的失败，在肢体发育过程中的结果。 这种表型在家族内以及在不相关的人之间可以有显著的差异。 表型的严重程度与LMX 1B突变之间没有相关性。 这种变异的基础必须起源于LIM 1B编码序列之外。 将鉴定控制LMX 1B表达的启动子元件以及与LMX 1B相互作用的分子。 将评估这些序列中表现出一系列表型严重性的家系中的变体。 还将确定羧基末端结构域是否在肢体发育中起作用。 将鉴定相互作用蛋白质，并分析缺乏该结构域的转基因小鼠。 这些信息可以帮助我们准确预测乳腺癌的严重程度。 这些实验不仅解决了单基因疾病中表型变异的问题，而且了解基因在表型发展中如何相互作用将有助于推导遗传复杂疾病的病因。 此外，通过鉴定控制LMX 1B表达的元件以及与LMX 1B相互作用的因子，将导出更好的肢体发育模型。