The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules.
Platelet dense granules are lysosome-related organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosome-related organelles is defective in inherited diseases such as Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. The platelet-dense granule defect is rescued in BAC transgenic mice containing the normal Slc35d3 gene. Thus, Slc35d3, an orphan member of a nucleotide sugar transporter family, specifically regulates the contents of platelet-dense granules. Unlike HPS or CHS genes, it has no apparent effect on other lysosome-related organelles such as melanosomes or lysosomes. The ash-Roswell mouse mutant is an appropriate model for human congenital-isolated delta-storage pool deficiency.
Chintala
Sreenivasulu
S
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Tan
Jian
J
Gautam
Rashi
R
Rusiniak
Michael E
ME
Guo
Xiaoli
X
Li
Wei
W
Gahl
William A
WA
Huizing
Marjan
M
Spritz
Richard A
RA
Hutton
Saunie
S
Novak
Edward K
EK
Swank
Richard T
RT
D000818:Animals; D001792:Blood Platelets / Q000648:ultrastructure*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D003594:Cytoplasmic Granules; D008247:Lysosomes; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000075745:rab27 GTP-Binding Proteins
D009004:Monosaccharide Transport Proteins; C518133:Slc35d3 protein, mouse; D000075745:rab27 GTP-Binding Proteins; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins