Role of Rab38G protein expressed in specifically in the lower respiratory epithelium in the interstitial lung disease

红宝石大鼠包括Fawn-Hooded和Long Evans Cinnamon/Crj（LEC/Crj），被称为Hermansky-Pudlak综合征的动物模型。我们从这些大鼠的尾部提取基因组DNA，进行DNA测序，发现Rab 38基因外显子1的翻译起始密码子发生点突变，导致ATG变为ATA，表明没有核酸翻译成氨基酸。对来自这些大鼠的肺组织裂解物的Western印迹分析证实不存在Rab 38蛋白。这些大鼠有红宝石样的暗红色眼睛和肉桂样的被毛，并显示出血时间延长至15分钟以上。因此，这些大鼠具有眼皮肤白化病。LEC/Crj肺呈肺气肿样改变，肺泡Ⅱ型细胞肿胀，胞浆板层体增多，体积增大。支气管肺泡灌洗液、板层体部分和总肺匀浆的蛋白质印迹分析显示，肺组织中表面活性蛋白B增加，但肺泡腔中减少。分离的肺泡II型细胞LEC/Crj显示减少基础分泌的[3 H]-rabeled表面活性剂磷脂酰胆碱，但显着增加激动剂诱导的分泌。这些结果表明，Rab 38缺乏导致大鼠眼皮肤白化病，出血素质和肺部疾病。由于这些表型与人类Hermansky-Pudlak综合征的表型相对应，因此认为Rab 38基因异常可能导致人类疾病。

Ruby rats including Fawn-Hooded and Long Evans Cinnamon/Crj (LEC/Crj) are known as animal model of Hermansky-Pudlak syndrome. We extracted genome DNA from tails of these rats, performed DNA sequence, and found a point mutation in the translation initiation codon in the exon 1 of Rab38 gene, resulting in ATG to ATA that indicates no translation of nucleic acids to amino acids. Western blot analysis on the lung tissue lysates from these rats confirmed no existence of Rab38 protein. These rats had ruby-like dark red eyes and cinnamon-like coat hairs, and showed elongation of bleeding time to more than 15 minutes. Thus, these rats have oculocutaneous albinism. The lungs of LEC/Crj showed emphysema-like appearance, and alveolar type II cells were swelled with cytoplasmic lammelar bodies increased in number and in size. Western blot analysis of bronchoalveolar lavage fluid, lamellar body fraction, and total lung homogenate showed that surfactant protein B was increased in the lung tissue but decreased in the alveolar lumen. Isolated alveolar type II cells from LEC/Crj showed decreased basal secretion of [3H]-rabeled surfactant phosphatidylcholine but remarkably increased agonist-induced secretion. These results indicate that Rab38 deficiency in the rat causes oculocutaneous albinism, bleeding diathesis, and lung disease. As these phenotypes correspond to those of human Hermansky-Pudlak syndrome, it is suggested that genetic abnormality of Rab38 may cause the disease in humans.