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Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice

Nature Genetics volume 30, pages 8185 (2002) | Download Citation



Pigmentary glaucoma is a significant cause of human blindness. Abnormally liberated iris pigment and cell debris enter the ocular drainage structures, leading to increased intraocular pressure (IOP) and glaucoma1,2,3. DBA/2J (D2) mice develop a form of pigmentary glaucoma involving iris pigment dispersion (IPD) and iris stromal atrophy (ISA)4,5. Using high-resolution mapping techniques, sequencing and functional genetic tests, we show that IPD and ISA result from mutations in related genes encoding melanosomal proteins. IPD is caused by a premature stop codon mutation in the Gpnmb (GpnmbR150X) gene, as proved by the occurrence of IPD only in D2 mice that are homozygous with respect to GpnmbR150X; otherwise, similar D2 mice that are not homozygous for GpnmbR150X do not develop IPD. ISA is caused by the recessive Tyrp1b mutant allele and rescued by the transgenic introduction of wildtype Tyrp1. We hypothesize that IPD and ISA alter melanosomes, allowing toxic intermediates of pigment production to leak from melanosomes, causing iris disease and subsequent pigmentary glaucoma. This is supported by the rescue of IPD and ISA in D2 eyes with substantially decreased pigment production. These data indicate that pigment production and mutant melanosomal protein genes may contribute to human pigmentary glaucoma. The fact that hypopigmentation profoundly alleviates the D2 disease indicates that therapeutic strategies designed to decrease pigment production may be beneficial in human pigmentary glaucoma.

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We thank F. Farley and J. Smith for assistance preparing the manuscript, C. Fickett and J. Martin for animal care; O. Savinova for technical assistance, and G. Cox, J. Naggert, and D. Gould for critical reading of the manuscript. This work was supported in part by grants from the National Institutes of Health. Scientific support services at The Jackson Laboratory are funded by a grant from the National Cancer Institute. Major funding was provided by the Howard Hughes Medical Institute. S.W.M.J. is an Assistant Investigator of The Howard Hughes Medical Institute.

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  1. The Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA.

    • Michael G. Anderson
    • , Richard S. Smith
    •  & Simon W.M. John
  2. The Jackson Laboratory, Bar Harbor, Maine 04609, USA.

    • Michael G. Anderson
    • , Richard S. Smith
    • , Norman L. Hawes
    • , Adriana Zabaleta
    • , Bo Chang
    •  & Simon W.M. John
  3. Department of Opthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.

    • Janey L. Wiggs
  4. Department of Ophthalmology, Tufts University School of Medicine, Boston 02111, Massachusetts, USA.

    • Simon W.M. John


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Correspondence to Simon W.M. John.

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