title: Genetic dissection of the Gpnmb network in the eye.
abstract: OBJECTIVE
  To use a systematic genetics approach to investigate the regulation of Gpnmb, a gene that contributes to pigmentary dispersion syndrome (PDS) and pigmentary glaucoma (PG) in the DBA/2J (D2) mouse.
  
  
  METHODS
  Global patterns of gene expression were studied in whole eyes of a large family of BXD mouse strains (n = 67) generated by crossing the PDS- and PG-prone parent (DBA/2J) with a resistant strain (C57BL/6J). Quantitative trait locus (eQTL) mapping methods and gene set analysis were used to evaluate Gpnmb coexpression networks in wild-type and mutant cohorts.
  
  
  RESULTS
  The level of Gpnmb expression was associated with a highly significant cis-eQTL at the location of the gene itself. This autocontrol of Gpnmb is likely to be a direct consequence of the known premature stop codon in exon 4. Both gene ontology and coexpression network analyses demonstrated that the mutation in Gpnmb radically modified the set of genes with which Gpnmb expression is correlated. The covariates of wild-type Gpnmb are involved in biological processes including melanin synthesis and cell migration, whereas the covariates of mutant Gpnmb are involved in the biological processes of posttranslational modification, stress activation, and sensory processing.
  
  
  CONCLUSIONS
  These results demonstrated that a systematic genetics approach provides a powerful tool for constructing coexpression networks that define the biological process categories within which similarly regulated genes function. The authors showed that the R150X mutation in Gpnmb dramatically modified its list of genetic covariates, which may explain the associated ocular pathology.
authors.affiliation: Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Xusheng
authors.initials: X
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: Pullen
authors.forename: Huaijin
authors.initials: H
authors.lastname: Guan
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Shwetapadma
authors.initials: S
authors.lastname: Sahu
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
authors.forename: Eldon E
authors.initials: EE
authors.lastname: Geisert
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Monica M
authors.initials: MM
authors.lastname: Jablonski
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D005123:Eye / Q000378:metabolism*; D005128:Eye Diseases / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005902:Glaucoma, Open-Angle / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation; D010859:Pigmentation Disorders / Q000235:genetics / Q000378:metabolism; D040641:Quantitative Trait Loci; D013577:Syndrome
chemical_list: D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D008562:Membrane Glycoproteins