| Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. | |
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MedLine Citation:
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PMID: 11743578 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 glaucoma. DBA/2J (D2) mice develop a form of pigmentary glaucoma involving iris pigment dispersion (IPD) and iris stromal atrophy (ISA). 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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Authors:
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Michael G Anderson; Richard S Smith; Norman L Hawes; Adriana Zabaleta; Bo Chang; Janey L Wiggs; Simon W M John |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. Date: 2001-12-17 |
Journal Detail:
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Title: Nature genetics Volume: 30 ISSN: 1061-4036 ISO Abbreviation: Nat. Genet. Publication Date: 2002 Jan |
Date Detail:
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Created Date: 2001-12-25 Completed Date: 2002-02-04 Revised Date: 2010-06-10 |
Medline Journal Info:
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Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: United States |
Other Details:
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Languages: eng Pagination: 81-5 Citation Subset: IM |
Affiliation:
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The Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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GENBANK/AC006949 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atrophy Chromosome Mapping Chromosomes, Artificial, Bacterial Codon, Nonsense Codon, Terminator Crosses, Genetic Epistasis, Genetic Eye Proteins / genetics* Genetic Predisposition to Disease Glaucoma, Open-Angle / genetics* Haplotypes Humans Iris / chemistry, pathology Melanosomes / metabolism* Membrane Glycoproteins / deficiency, genetics* Mice Mice, Inbred C57BL Mice, Inbred DBA Molecular Sequence Data Oxidoreductases* Pigments, Biological / metabolism* Proteins / genetics* Recombination, Genetic Specific Pathogen-Free Organisms |
| Chemical | |
Reg. No./Substance:
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0/Codon, Nonsense; 0/Codon, Terminator; 0/Eye Proteins; 0/Gpnmb protein, mouse; 0/Membrane Glycoproteins; 0/Pigments, Biological; 0/Proteins; EC 1.-/Oxidoreductases; EC 1.14.18.-/TYRP1 protein, human; EC 1.14.18.-/Tyrp1 protein, mouse; EC 1.14.18.-/tyrosinase-related protein-1 |
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