Mouse Pale Ear (ep) is Homologous to Human Hermansky-Pudlak Syndrome and Contains a Rare 'AT-AC' Intron

Abstract

Hermansky-Pudlak syndrome (HPS) is a rare, often fatal, autosomal recessive disorder in which albinism, bleeding and lysosomal storage are associated with defects of diverse cytoplasmic organelles, including melanosomes, platelet dense granules and lysosomes. Similar multi-organellar defects occur in the Chediak-Higashi syndrome (CHS), as well as in a large number of different mouse mutants. The HPS gene is located in 10q23, and two genetically distinct mouse loci, pale ear (ep) and ruby-eye (ru), both with mutant phenotypes similar to human HPS, map close together in the homologous region of murine chromosome 19, suggesting that one of these loci might be homologous to human HPS. We recently identified the human HPS gene, which encodes a novel ubiquitously-expressed transmembrane protein of unknown function. Here, we describe characterization of the mouse Hps cDNA and genomic locus, and identification of pathologic Hps gene mutations in ep but not in ru mice, establishing mouse pale ear as an animal model for human HPS. The phenotype of homozygous ep mutant mice encompasses those of both HPS and CHS, suggesting that these disorders may be closely related. In addition, the mouse and human HPS genes both contain a rare 'AT-AC' intron, and comparison of the sequences of this intron in the mouse and human genes identified conserved sequences that suggest a possible role for pre-mRNA secondary structure in excision of this rare class of introns.

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

“…Mice have more than 16 different genes with HPS-like phenotypes (40), although many of the gene functions are unknown. At least six mouse models have the orthologous mutations to the human genes (41)(42)(43)(44)(45)(46). Interestingly, murine models of HPS-1 (Pale ear) and HPS-2 (Pearl) show activation of alveolar macrophages in the lung, but not in the blood or peritoneum (47,48).…”

Identification of a Novel Human Tankyrase through Its Interaction with the Adaptor Protein Grb14

“…Finally, an intriguing observation in relation to the potential role of tankyrase 2 in regulating vesicle dynamics is that a region of mouse chromosome 19 syntenic with human chromosome 10q23 (which harbors TANKYRASE 2, Fig. 2) contains two loci, pale ear (ep) and ruby-eye (ru), responsible for phenotypes similar to human Hermansky-Pudlak syndrome, a condition associated with defects in multiple cytoplasmic organelles, including lysosomes (44,45). The ep locus corresponds to the human gene HPS, which is mutated in a subset of Hermansky-Pudlak syndrome patients (45).…”

“…2) contains two loci, pale ear (ep) and ruby-eye (ru), responsible for phenotypes similar to human Hermansky-Pudlak syndrome, a condition associated with defects in multiple cytoplasmic organelles, including lysosomes (44,45). The ep locus corresponds to the human gene HPS, which is mutated in a subset of Hermansky-Pudlak syndrome patients (45). However, the gene responsible for the defect in ru mice remains to be identified, and our studies highlight Tankyrase 2 as a candidate.…”

BLOC-3, a Protein Complex Containing the Hermansky-Pudlak Syndrome Gene Products HPS1 and HPS4

“…Another human disorder, Hermansky-Pudlak syndrome (HPS), results from mutations in either one of six genes designated HPS1-HPS6 (5)(6)(7)(8)(9). Mutations in the orthologous genes have been identified in the mouse coat color mutants, pale ear (HPS1 (10,11)), pearl (HPS2 (12)), cocoa (HPS3 (13)), light ear (HPS4 (8)), ruby eye-2 (HPS5 (9)), and ruby eye (HPS6 (9)), which serve as animal models for the human disease. Other studies have led to the identification of additional genes mutated in other mouse models of HPS, including mocha (14), gunmetal (15), buff (16), pallid (17), muted (18), and cappuccino (19).…”