Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease affecting the biogenesis of lysosomes and lysosome-related organelles, including melanosomes and platelet-dense granules. Clinical features include oculocutaneous hypopigmentation, fibrotic lung disease, and prolonged bleeding times. Mouse HPS mutants are a rich source of these genes (at least 16), and thus far, mutations in 6 orthologous genes have been found in HPS patients (Zhang et al, Nat Genet. 2003;33:145-153).
Positional cloning strategies combining large interspecific mouse backcrosses and the ability to mine mouse and human genes by computer have accelerated identifications of HPS genes. In this issue, Ciciotte and colleagues (page 4402) significantly advance our understanding of HPS by using these approaches to identify the cappuccino mouse HPS gene (cno), a novel gene found only in higher metazoans. Cno is a member of a growing list (8) of novel HPS genes that apparently have evolved in higher organisms to regulate the synthesis of specialized subcellular organelles. This conclusion is consistent with the fact that specialized mammalian organelles such as platelet-dense granules and melanosomes are not found in lower eukaryotes such as yeast. Further, Ciciotte et al have determined that the cno protein occurs in a common protein complex (BLOC-1) with the muted and pallid HPS proteins. That these proteins are members of a common complex agrees with the fact that the phenotypes of these mouse mutants are highly similar (Nguyen et al, J Invest Dermatol. 2002;119:1156-1164). Also, their phenotypes are among the most severe of any mouse HPS mutants, under-scoring the importance of the BLOC-1 complex in the genesis of lysosome-related organelles. An emerging theme is that many HPS proteins function as members of communal protein complexes, although the exact mechanisms by which these complexes control the biosynthesis of lysosome-related organelles remain uncertain.
The long-term hope is that the identification of the cno gene and related advances will lead to useful therapies for this debilitating, sometimes deadly, and presently incurable inherited disease of specialized lysosome-related organelles.
