Epidemiology of Surfactant Protein-B Deficiency

描述（由申请人提供）：表面活性剂蛋白B缺乏是由于表面活性剂蛋白5基因（SFTPB）罕见的、纯合的、功能丧失突变导致的，不可避免地导致致命的新生儿呼吸窘迫综合征。非致死性基因变异不能解释有症状婴儿表面活性剂蛋白B肽表达的所有变化。表面活性剂蛋白C基因（SFTPC）的遗传变异也可能导致SFTPB表达的中断。人类和小鼠研究表明，生物合成路线、翻译后加工和表面活性剂蛋白B和C的肺表面活性剂功能之间存在紧密联系。显性负突变编码的折叠或错标表面活性剂蛋白C肽通过形成细胞内聚集体和/或保留在内质网中触发2型肺细胞的未折叠蛋白反应。破坏肺表面活性剂的细胞内运输，并中断表面活性剂蛋白B的分泌。为了确定SFTPC基因变异对表面活性剂蛋白B缺乏风险的贡献，我们将检验SFTPB和SFTPC基因-基因相互作用增加新生儿呼吸窘迫风险的假设。为了避免由于种族分层、环境选择或基因型-表型异质性而可能夸大或低估罕见遗传变异频率的小患者群体外推，我们设计了有症状和无症状婴儿的描述性和病例对照研究，这些研究将提供足够的统计功率（0.8），以确定与新生儿呼吸窘迫综合征相关的SFTPB和SFTPC的变异和单倍型组合。具体来说，在描述性研究中，我们将在密苏里州未选择的、去识别的、基于人群的婴儿队列（N= 1116）中，使用SFTPB和SFTPC的高通量自动测序和相关的基于生命统计学的表型数据，确定基因型或单倍型与新生儿呼吸窘迫之间的关系。在病例对照研究（N=480）中，使用SFTPB和SFTPC的自动测序以及临床和生化表型数据，我们将确定基因-基因相互作用是否会减少或改变表面活性剂蛋白B的表达。这些研究将为新生儿呼吸窘迫综合征的诊断和治疗提供新的策略，以改善婴儿的预后。新生儿呼吸窘迫综合征是婴儿死亡的一个主要原因。使用最先进的方法来分析遗传密码，我们将确定两个基因之间的相互作用是否使婴儿易患呼吸窘迫。这些研究将为新生儿呼吸窘迫的诊断、治疗和预防提供新的策略。

DESCRIPTION (provided by applicant): Surfactant protein B deficiency due to rare, homozygous, loss of function mutations in the surfactant protein 5 gene (SFTPB) invariably causes lethal, neonatal respiratory distress syndrome. Non lethal genetic variants do not account for all changes in expression of surfactant protein B peptides in symptomatic infants. Disruption of SFTPB expression may also be caused by genetic variants in the surfactant protein C gene SFTPC). Human and murine studies have demonstrated tight linkage between the biosynthetic itineraries, post-translational processing, and functions in the pulmonary surfactant of surfactant proteins B and C. vlisfolded or mistargeted surfactant protein C peptides encoded by dominant negative mutations trigger the unfolded protein response in type 2 pneumocytes by formation of intracellular aggregates and/or retention in the endoplasmic reticulum, disrupt intracellular trafficking of the pulmonary surfactant, and interrupt surfactant protein B secretion. To determine the contribution of genetic variation in SFTPC to risk of surfactant protein B deficiency, we will test the hypothesis that gene - gene interactions between SFTPB and SFTPC increase risk of neonatal respiratory distress. To avoid extrapolation from small patient groups that may exaggerate or underestimate frequency estimates of rare genetic variants due to ethnic stratification, environmental selection, or genotype-phenotype heterogeneity, we have designed descriptive and case-control studies of symptomatic and asymptomatic infants that will provide sufficient statistical Dower (0.8) to identify combinations of variants and haplotypes in SFTPB and SFTPC associated with neonatal respiratory distress syndrome. Specifically, in the descriptive study, using high throughput automated sequencing of SFTPB and SFTPC and linked vital statistics-based phenotype data, we will determine associations between genotypes or haplotypes and neonatal respiratory distress in an unselected, de-identified, population-based cohort of Missouri infants (N=1,116). In the case-control study (N=480), using automated sequencing of SFTPB and SFTPC and both clinical and biochemical phenotype data, we will determine whether gene-gene interactions reduce or alter surfactant protein B expression. These studies will suggest new strategies for diagnosis and treatment of neonatal respiratory distress syndrome to improve infant outcomes. Neonatal respiratory distress syndrome is a major cause of infant mortality. Using state of the art methods for analyzing genetic code, we will determine whether interactions between 2 genes predispose infants to respiratory distress. These studies will suggest new strategies for diagnosis, treatment, and prevention of neonatal respiratory distress.