A Mutation in Rab38 Small GTPase Causes Abnormal Lung Surfactant Homeostasis and Aberrant Alveolar Structure in Mice

Abstract

The chocolate mutation, which is associated with oculocutaneous albinism in mice, has been attributed to a G146T transversion in the conserved GTP/GDP-interacting domain of Rab38, a small GTPase that regulates intracellular vesicular trafficking. Rab38 displays a unique tissue-specific expression pattern with highest levels present in the lung. The purpose of this study was to characterize the effects of Rab38-G146T on lung phenotype and to investigate the molecular basis of the mutant gene product (Rab38 cht protein). Chocolate lungs exhibited a uniform enlargement of the distal airspaces with mild alveolar destruction as well as a slight increase in lung compliance. Alveolar type II cells were engorged with lamellar bodies of increased size and number. Hydrophobic surfactant constituents (ie, phosphatidylcholine and surfactant protein B) were increased in lung tissues but decreased in alveolar spaces, consistent with a malfunction in lamellar body secretion and the subsequent cellular accumulation of these organelles. In contrast to wild-type Rab38, native Rab38 cht proteins were found to be hydrophilic and not bound to intracellular membranes. Unexpectedly, recombinant Rab38 cht proteins retained GTP-binding activity but failed to undergo prenyl modification that is required for membranebinding activity. These results suggest that the genetic abnormality of Rab38 affects multiple lysosome-related organelles , resulting in lung disease in addition to oculocutaneous albinism. (Am J

Altered lung surfactant system in a Rab38-deficient rat model of Hermansky-Pudlak syndrome

“…The lung involvement in HPS patients is characterized by usual interstitial pneumonia (UIP)-like interstitial pneumonia (16). However, rodent models of HPS develop hyperinflationary lungs (14,15,23) as seen in this study (Fig. 2) instead of fibrotic lungs, although its mechanism is not clarified yet.…”

“…Large airways and vessels were excluded from the analysis. Based on the lung morphometric method (23,30), the mean linear intercept (Lm), which represents average interalveolar distance, was calculated.…”

“…Chocolate mice, carrying another Rab38 mutation, showed altered lung surfactant homeostasis and alveolar structural derangement (23). These mice have oculocutaneous albinism but not bleeding diathesis, and hence it has been questioned whether they are an animal model of HPS.…”

Myosin Vc Interacts with Rab32 and Rab38 Proteins and Works in the Biogenesis and Secretion of Melanosomes

“…Rab32 and Rab38 are expressed in a tissue-specific manner, are chiefly present in LRO-producing cell types, and provide an elegant mechanistic explanation to the repurposing of the ubiquitous trafficking machinery for LRO biogenesis in specialized cell types (25,(27)(28)(29)(30)(31)(32). Consistently, rodents with mutations in Rab38 manifest with typical LRO deficiencies such as hypopigmentation due to impaired melanosome biogenesis (29,(31)(32)(33)(34)(35).…”

Genomic landscape of positive natural selection in Northern European populations

“…Of the two examples visualized as median-joining networks, the RAB38 gene is expressed in melanocytes, and its disruption in mice causes oculocutaneous albinism, lung disease, and platelet deficiency. [29][30][31] This makes RAB38 an interesting novel candidate locus for human pigmentation. The PPP2R2B gene regulates neuronal apoptosis and may affect adenovirus replication.…”