Document Detail

Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice.
MedLine Citation:
PMID:  11743578     Owner:  NLM     Status:  MEDLINE    
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.
Michael G Anderson; Richard S Smith; Norman L Hawes; Adriana Zabaleta; Bo Chang; Janey L Wiggs; Simon W M John
Related Documents :
23176758 - Association of nitric oxide synthase gene polymorphisms (-786t>c, 4a4b, 894g>t) with pr...
23164758 - Association of inflammatory bowel disease with familial mediterranean fever in turkish ...
23317308 - Hla-drb and hla-dqa/hla-dqb allele and haplotype frequencies in iranian patients with a...
17039978 - Early onset charcot-marie-tooth disease caused by a homozygous leu239phe mutation in th...
15367128 - Genetic structure, phylogeography and demography of two ground-beetle species endemic t...
25345968 - Genetic depletion at adaptive but not neutral loci in an endangered bird species.
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2001-12-17
Journal Detail:
Title:  Nature genetics     Volume:  30     ISSN:  1061-4036     ISO Abbreviation:  Nat. Genet.     Publication Date:  2002 Jan 
Date Detail:
Created Date:  2001-12-25     Completed Date:  2002-02-04     Revised Date:  2010-06-10    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  81-5     Citation Subset:  IM    
The Howard Hughes Medical Institute, Bar Harbor, Maine 04609, USA.
Data Bank Information
Bank Name/Acc. No.:
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Chromosome Mapping
Chromosomes, Artificial, Bacterial
Codon, Nonsense
Codon, Terminator
Crosses, Genetic
Epistasis, Genetic
Eye Proteins / genetics*
Genetic Predisposition to Disease
Glaucoma, Open-Angle / genetics*
Iris / chemistry,  pathology
Melanosomes / metabolism*
Membrane Glycoproteins / deficiency,  genetics*
Mice, Inbred C57BL
Mice, Inbred DBA
Molecular Sequence Data
Pigments, Biological / metabolism*
Proteins / genetics*
Recombination, Genetic
Specific Pathogen-Free Organisms
Reg. No./Substance:
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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia...
Next Document:  Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease ty...