Journal article
Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice
Nature genetics, Vol.30(1), pp.81-85
01/2002
DOI: 10.1038/ng794
PMID: 11743578
Abstract
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.
Details
- Title: Subtitle
- Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice
- Creators
- Adriana Zabaleta - The Jackson LaboratorySimon W.M John - The Howard Hughes Medical Institute The Jackson Laboratory Department of Ophthalmology, Tufts University School of MedicineMichael G Anderson - The Howard Hughes Medical Institute The Jackson LaboratoryRichard S Smith - The Howard Hughes Medical Institute The Jackson LaboratoryBo Chang - The Jackson LaboratoryNorman L Hawes - The Jackson LaboratoryJaney L Wiggs - Department of Opthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.30(1), pp.81-85
- DOI
- 10.1038/ng794
- PMID
- 11743578
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Language
- English
- Date published
- 01/2002
- Academic Unit
- Molecular Physiology and Biophysics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984025571702771
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