Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules [1][2][3] . In mice, at least 16 loci are associated with HPS 4-6 , including sandy (sdy ; ref. 7 ). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to α-and β-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells 8 . We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 ), which regulates Correspondence should be addressed to R.T.S (richard.swank@roswellpark.org). 11 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Genetics website. Competing Interests Statement:The authors declare that they have no competing financial interests. We previously showed 7 that the sdy mutant mouse is a valid model for human HPS and localized the gene sdy to mouse chromosome 13. Here we genotyped 20 microsatellite markers in 1,250 progeny of sdy backcrosses to localize sdy to the 2.2-cM interval between D13Mit244 and D13Mit267 (Fig. 1). We identified the sdy interval within a 28-Mb scaffold (Celera Discovery System) containing two known genes, Jmj and Dtnbp1 (Fig. 1b). We used PCR products of D13Mit179 and the Dtnbp1 cDNA as probes to generate a BAC contig covering the sdy interval (Fig. 1b). NIH Public AccessNorthern-blot analysis and sequencing of RT-PCR products of Jmj identified no abnormalities in sdy mutants, but truncated genomic PCR products (Fig. 2a) and mRNA ( Fig. 2b) of Dtnbp1 were apparent in sdy tissues. Sequencing of RT-PCR products showed that exons 6 and 7 (156 bp) of Dtnbp1 were deleted in mutant mice, resulting in the loss of 52 amino acids from position 119-172 of the dysbindin protein ( Supplementary Fig. 1 online). Genomic sequencing showed that this results from a large deletion (38,129 bp) from nucleotide 3,701 of intron 5 to nucleotide 12,377 of intron 7. This deletion was not found in twelve other inbred mouse strains (Fig. 2a), including coisogenic DBA/2J, indicating that it was not a strain-specific polymorphism. This in-frame deletion creates a 1.5-kb mutant dysbindin transcript ( Fig. 2b) and abolishes expression of the 51-kDa dysbindin 8 protein in sdy/sdy mice ( Fig. 2c). Expression of dysbindin is restored in sdy/sdy transgenic mice containing BAC54F9 (Fig. 2c). Platelet serotonin levels of six of these transgenics were normal (>1.12 μg per 10 9 platelets), whereas all five sdy/sdy litter-mates without BAC54F9 had platelet serotonin levels of <0.06 μg per 10 9 platelets. sdy/sdy progeny containing the BAC transgene had dar...

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles.

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SPARC is a Mr 43,000 secreted, acidic, cysteine‐rich glycoprotein homologous to 43K bovine endothelial ‘culture shock’ protein. We show here that it is encoded by a single gene localized to the central region of mouse chromosome 11. During development SPARC mRNA is expressed at higher levels in all the extra‐embryonic tissues than in the fetus. Highest levels are found in the parietal endoderm, while visceral endoderm has approximately 6‐fold less. This differential expression is also seen in F9 teratocarcinoma cells treated with retinoic acid under conditions in which they give rise to either parietal or visceral endoderm. The 20‐fold increase seen during differentiation into parietal endoderm is due, at least in part, to an increase in gene transcription. We also report SPARC expression in a variety of adult tissues and cultured cells, and present evidence that a decrease accompanies the transformation of fibroblast cell lines.

The beige mouse is an animal model for the human Chediak-Higashi syndrome, a disease characterized by giant lysosomes in most cell types. In mice, treatment with androgenic hormones causes a 20-50-fold elevation in at least one kidney lysosomal enzyme, ~-glucuronidase. Beige mice treated with androgen had significantly higher kidney ~-glucuronidase, B-galactosidase, and N-acetyl-~-oglucosaminidase (hexosaminidase) levels than normal mice. Other androgeninducible enzymes and enzyme markers for the cytosol, mitochondria, and peroxisomes were not increased in kidney of beige mice. No significant lysosomal enzyme elevation was observed in five other organs of beige mice with or without androgen treatment, nor in kidneys of beige females not treated with androgen.Histochemical staining for glucuronidase together with subcellular fractionation showed that the higher glucuronidase content of beige mouse kidney is caused by a striking accumulation of giant glucuronidase-containing iysosomes in tubule cells near the corticomedullary boundary. In normal mice lysosomal enzymes are coordinately released into the lumen of the kidney tubules and appreciable amounts of lysosomal enzymes are present in the urine. Levels of urinary lysosomal enzymes are much lower in beige mice than in normal mice.