Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation

Sci Rep. 2017 Jan 6:7:39933. doi: 10.1038/srep39933.

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 LMX1BR246Q causes a renal-specific phenotype is unknown. In this study, using human podocyte cell lines overexpressing either myc-LMX1BWT or 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 LMX1BR246Q mutation 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cell Line
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 9 / genetics
  • Down-Regulation*
  • Exome Sequencing
  • Female
  • Gene Expression Regulation
  • Genetic Linkage
  • Haploinsufficiency
  • Humans
  • LIM-Homeodomain Proteins / genetics*
  • Male
  • Mutation, Missense*
  • Nail-Patella Syndrome / genetics*
  • Nephritis, Hereditary / genetics*
  • Pedigree
  • Podocytes / cytology*
  • Transcription Factors / genetics*
  • WT1 Proteins / genetics*
  • Young Adult

Substances

  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • Transcription Factors
  • WT1 Proteins
  • WT1 protein, human

Supplementary concepts

  • Salcedo syndrome