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Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6

Nature Genetics volume 33, pages 145–153 (2003)Cite this article

Abstract

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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Figure 1: High-resolution genetic (a,c) and physical (b,d) maps of the ru2 and ru regions of mouse chromosomes 7 and 19.
Figure 2: Transgenic 'rescue' of ru2 and ru.
Figure 3: Transcripts of the ru6J allele are abnormally expressed in kidney and brain.
Figure 4: Alignment of mouse ru2 (a) and ru (b) sequences with orthologous sequences from other species.
Figure 5: Melanosomes of the retinal pigment epithelium (RPE) and choroid (CH) are quantitatively and qualitatively abnormal in eyes of ruby-eye 2 and ruby-eye mutants.
Figure 6: The ru2 and ru proteins are components of a complex.
Figure 7: The ru2 and ru proteins directly interact.

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Acknowledgements

We thank M. Reddington, L. Zhen, Y. Jiang, D. Poslinski, D. Tabaczynski, M. Ellsworth, J. Pazik, and J. Tan for technical assistance; D. Swing for the microinjection; L. Gagnon for helping with the JE/Le cross; Y. Ni, X. Jiang and L. Song for sequencing BACs; and H. Chen for assistance in 5′ RACE analysis of ru2. P. Graf, C. McGregor and D. Ako-Adjei contributed to the construction of the ru genetic map. We thank H. Baumann for the gift of the STAT3 construct. This work was supported in part by the National Institutes of Health (R.T.S., E.M.E., B.A.R. and R.A.S.) and by the National Cancer Institute, Department of Health and Human Services (N.G.C. and N.A.J.). This research used core facilities supported in part by Roswell Park Cancer Institute's National Cancer Institute–funded Cancer Center Support Grant and by the Cancer Core Grant of The Jackson Laboratory.

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Author notes

  1. Qing Zhang, Baohui Zhao, Wei Li and Naoki Oiso: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, 14263, New York, USA

    Qing Zhang, Baohui Zhao, Wei Li, Edward K. Novak, Michael E. Rusiniak, Rashi Gautam, Sreenivasulu Chintala, Edward P. O'Brien, Yuke Zhang, Rosemary W. Elliott & Richard T. Swank

  2. Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, 80262, Colorado, USA

    Naoki Oiso & Richard A. Spritz

  3. Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA

    Bruce A. Roe

  4. The Jackson Laboratory, Bar Harbor, Maine, USA

    Eva M. Eicher

  5. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA

    Ping Liang

  6. Klinik für Pädiatrische Hämatologie und Onkologie, Heinrich-Heine-Universität, Düsseldorf, Germany

    Christian Kratz

  7. Center for Human Genetics, Universitaire Ziekenhuizen, Leuven, Leuven, Belgium

    Eric Legius

  8. Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, USA

    T. Norene O'Sullivan, Neal G. Copeland & Nancy A. Jenkins

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Correspondence to Richard T. Swank.

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Zhang, Q., Zhao, B., Li, W. et al. Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6. Nat Genet 33, 145–153 (2003). https://doi.org/10.1038/ng1087

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