title: Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation.
abstract: Mutations in the LIM homeobox transcription factor 1-beta (LMX1B) are a cause of nail patellar syndrome, a condition characterized by skeletal changes, glaucoma and focal segmental glomerulosclerosis. Recently, a missense mutation (R246Q) in LMX1B was reported as a cause of glomerular pathologies without extra-renal manifestations, otherwise known as nail patella-like renal disease (NPLRD). We have identified two additional NPLRD families with the R246Q mutation, though the mechanisms by which LMX1BR246Qcauses a renal-specific phenotype is unknown. In this study, using human podocyte cell lines overexpressing either myc-LMX1BWTor myc-LMX1BR246Q, we observed dominant negative and haploinsufficiency effects of the mutation on the expression of podocyte genes such as NPHS1, GLEPP1, and WT1. Specifically, we observed a novel LMX1BR246Q-mediated downregulation of WT1(-KTS) isoforms in podocytes. In conclusion, we have shown that the renal-specific phenotype associated with the LMX1BR246Qmutation may be due to a dominant negative effect on WT1(-KTS) isoforms that may cause a disruption of the WT1 (-KTS):(+KTS) isoform ratio and a decrease in the expression of podocyte genes. Full delineation of the LMX1B gene regulon is needed to define its role in maintenance of glomerular filtration barrier integrity.
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.|Division of Nephrology, Duke University Medical Center, Durham, NC, United States.
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.|Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Lane
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.|Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Megan
authors.initials: M
authors.lastname: Chryst-Ladd
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.|Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Wake Forest Baptist Medical Center, Winston Salem, NC, United States.
authors.forename: Jen-Jar
authors.initials: JJ
authors.lastname: Lin
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.
authors.forename: XueJun
authors.initials: X
authors.lastname: Qin
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Hauser
authors.affiliation: Duke Molecular Physiology Institute, Durham, NC, United States.|Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
authors.forename: Rasheed
authors.initials: R
authors.lastname: Gbadegesin
mesh_terms: D000293:Adolescent; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D057895:Haploinsufficiency; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009261:Nail-Patella Syndrome / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000235:genetics*; D010375:Pedigree; D050199:Podocytes / Q000166:cytology*; D014157:Transcription Factors / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics*; D000073359:Exome Sequencing; D055815:Young Adult
chemical_list: C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D025721:WT1 Proteins; C583751:WT1 protein, human