Rodriguez-Gil Jorge L, Watkins-Chow Dawn E, Baxter Laura L, Yokoyama Tadafumi, Zerfas Patricia M, Starost Matthew F, Gahl William A, Malicdan May Christine V, Porter Forbes D, Platt Frances M, Pavan William J
Genomics, Development and Disease Section, Genetic Disease Research Branch, NHGRI, NIH, Bethesda, MD, 20892, USA.
Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
J Clin Med. 2019 Dec 19;9(1):12. doi: 10.3390/jcm9010012.
The rare lysosomal storage disorder Niemann-Pick disease type C1 (NPC1) arises from mutation of , which encodes a lysosomal transmembrane protein essential for normal transport and trafficking of cholesterol and sphingolipids. NPC1 is highly heterogeneous in both clinical phenotypes and age of onset. Previous studies have reported sub-Mendelian survival rates for mice homozygous for various mutant alleles but have not studied the potential mechanisms underlying this phenotype. We performed the first developmental analysis of a mouse model, , and discovered significant fetal growth restriction in homozygous mutants beginning at E16.5. mice also exhibited cyanosis, increased respiratory effort, and over 50% lethality at birth. Analysis of neonatal lung tissues revealed lipid accumulation, notable abnormalities in surfactant, and enlarged alveolar macrophages, suggesting that lung abnormalities may be associated with neonatal lethality in mice. The phenotypic severity of the model facilitated this first analysis of perinatal lethality and lung pathology in an NPC1 model organism, and this model may serve as a useful resource for developing treatments for respiratory complications seen in NPC1 patients.
罕见的溶酶体贮积症C1型尼曼-皮克病（NPC1）由 基因突变引起，该基因编码一种溶酶体跨膜蛋白，对胆固醇和鞘脂的正常转运至关重要。NPC1在临床表型和发病年龄上具有高度异质性。先前的研究报道了各种突变等位基因纯合小鼠的亚孟德尔生存率，但尚未研究这种表型背后的潜在机制。我们对一种小鼠模型 进行了首次发育分析，发现纯合突变体从E16.5开始出现显著的胎儿生长受限。 小鼠还表现出发绀、呼吸费力增加，出生时死亡率超过50%。对新生小鼠肺组织的分析显示有脂质蓄积、表面活性剂明显异常以及肺泡巨噬细胞增大，提示肺部异常可能与 小鼠的新生儿致死率有关。 模型的表型严重程度有助于对NPC1模式生物中的围产期致死率和肺部病理学进行首次分析，该模型可能为开发治疗NPC1患者所见呼吸并发症的方法提供有用资源。
