The paper by Chintala and colleagues provides new insights into what was once considered an animal model for Hermansky-Pudlak syndrome (HPS), a hereditary disorder involving platelet dense bodies. In an exquisite piece of detective work, it resolves a serious question about whether the ashen mutant mouse should be considered a model for HPS. In so doing, the study provides an excellent example of the value of high-quality collaborative research and points to a possible role for a putative sugar antiporter in the biogenesis or function of platelet dense bodies.
The ashen mouse is one among several naturally occurring autosomal recessive hypopigment mutant strains. Some 15 of these are considered animal models for Hermansky-Pudlak syndrome (HPS) as they share phenotypic manifestations including partial albinism and prolonged bleeding times. Eight of these have the same mutant genes in HPS patients. Prolonged bleeding times are due to faulty platelet aggregation caused by the lack or dysfunction of platelet dense bodies.
In the strain of ashen mutants maintained at the Roswell Park Cancer Institute, the animals had both the pigment and platelet defects, whereas animals of the original strain from Jackson Laboratories did not exhibit the platelet defect. Both strains were mutant for rab27a, so it was thought that this gene may have pleiotropic effects and the strain was considered an HPS animal model. Repeated attempts, however, failed to resolve the discrepancy of the platelet abnormality between the 2 strains using serotonin levels as a marker for dense bodies. Hence, Chintala and colleagues performed their investigations to determine the genetic differences between the 2 strains.
The authors were able to separate the platelet defect of the Roswell Park ashen mutants from the hypopigment phenotype by appropriate crosses, to localize the gene responsible for the platelet defect by positional cloning, and to rescue this defect with high probability in transgenic mice using BAC for gene transfer into mutant oocytes. Once the gene for the platelet defect was determined, they examined several HPS patients of unknown etiology for possible mutations in this gene, but found none.
This was a complex undertaking and required the expertise of 3 laboratories—at Roswell Park for the crosses and analyses of platelet function, the University of Colorado Health Sciences Center for positional cloning and production of transgenic mice, and the National Institutes of Health for the analyses of HPS patients. Their results are ground breaking. The platelet defect seen in the Roswell ashen strain is caused by a mutation in a putative sugar antiporter locus, Scl35d3, which establishes that the gene product plays an important role in platelet dense body formation or function. Also, the gene product affects platelet dense bodies but not melanosomes, apparently excluding Scl35d3 as an HPS locus.
Future work must determine the nature and role of the Scl35d3 gene product. Its mutant transcript is overexpressed, and the mutation in the Roswell ashen strain is due to an IAP insertion disrupting the normal N-terminus amino acids. The research of Chintala et al provides the background and direction for further study of this protein in normal platelet functions.
The author declares no competing financial interests. ▪
