A mutation in Rab38 small GTPase causes abnormal lung surfactant homeostasis and aberrant alveolar structure in mice.
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 membrane-binding activity. These results suggest that the genetic abnormality of Rab38 affects multiple lysosome-related organelles, resulting in lung disease in addition to oculocutaneous albinism.
Osanai
Kazuhiro
K
Department of Respiratory Medicine, Kanazawa Medical University, Kahokugun, Ishikawa 920-0293, Japan. k-osanai@kanazawa-med.ac.jp
Oikawa
Rieko
R
Higuchi
Junko
J
Kobayashi
Makoto
M
Tsuchihara
Katsuma
K
Iguchi
Masaharu
M
Jongsu
Huang
H
Toga
Hirohisa
H
Voelker
Dennis R
DR
D000417:Albinism / Q000235:genetics; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009929:Organ Size; D010641:Phenotype; D054876:Prenylation; D011312:Pressure; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D011663:Pulmonary Surfactants / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics*
D011663:Pulmonary Surfactants; D006160:Guanosine Triphosphate; C498786:Rab38 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D020691:rab GTP-Binding Proteins