Survival and lung pathology of mouse models of Hermansky-Pudlak Syndrome and Chediak-Higashi Syndrome

Hermansky-Pudlak Syndrome (HPS), a recessively inherited disease in humans, affects the biosynthesis/processing of the related intracellular organelle s: lysosomes, melanosomes, and platelet dense granules. The disease is mult igenic in both humans and mice where 14 separate genes have been demonstrat ed to be causative. Patients often die prematurely with severe lung abnorma lities. Patients with the related Chediak-Higashi Syndrome (CHS) likewise h ave significantly reduced life spans. Long-term survival and lung histomorp hology were analyzed in a pilot experiment involving several genetically de fined singly and doubly mutant mouse HPS mutants and the beige CHS mutant t o determine whether these parameters are altered in the mouse models. The m utants differed widely in both longevity and lung architecture. Mice doubly homozygous for the pale ear and ruby eye or for the muted and pearl genes had the shortest life spans with none surviving the two-year experimental d uration, Life spans were similarly severely reduced in the beige and gunmet al mutants. Intermediate life spans were apparent in the pearl, pallid, and cocoa mutants whereas minimal effects were noted in ruby eye, muted, light ear, and cocoa mutants. Enlarged air spaces were noted in histologic secti ons of lungs of several of the mutants. For the most part, the severity of lung abnormalities was inversely proportional to the long-term survival of these various mutants, suggesting that lung pathology may contribute to mor tality, as has been suggested for human HPS patients.