MOLECULAR GENETICS OF NAIL PATELLA SYNDROME

指甲髌骨综合征的分子遗传学

• 批准号: 6511895
• 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/6511895
• 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 (NPS) 是一种以常染色体显性方式遗传的多种表型。 该综合征的特点是指甲、髌骨和肘部发育不良，以及开角型青光眼和潜在致命性肾病。 已经确定 NPS 是 LIM 同源域转录因子 LMX1B 杂合功能丧失突变的结果。 迄今为止发现的 NPS 突变集中在 LIM 和同源域内；在编码区的羧基末端三分之一内没有发现任何一个。 与动物模型的比较表明，与 NPS 相关的骨科问题是由于肢体发育过程中背侧化失败造成的。 NPS 表型在家庭内部以及无关人员之间可能存在显着差异。 表型的严重程度与 LMX1B 突变之间没有相关性。 这种变异的基础必须源自 LIM1B 编码序列之外。 将鉴定控制 LMX1B 表达的启动子元件以及与 LMX1B 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程度的 NPS 家族中的变异。 还将确定羧基末端结构域是否在四肢发育中发挥作用。 将鉴定相互作用的蛋白质并分析缺乏该结构域的转基因小鼠。 该信息可以准确预测 NPS 严重程度。 这些实验不仅将解决单基因疾病内的表型变异问题，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状况的病因学。 此外，通过识别控制LMX1B表达的元件以及与LMX1B相互作用的因素，将得出更好的肢体发育模型。