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

Publication ,  Journal Article
Hall, G; Lane, B; Chryst-Ladd, M; Wu, G; Lin, J-J; Qin, X; Hauser, ER; Gbadegesin, R
Published in: Sci Rep
January 6, 2017

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.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

January 6, 2017

Volume

7

Start / End Page

39933

Location

England

Related Subject Headings

  • Young Adult
  • WT1 Proteins
  • Transcription Factors
  • Podocytes
  • Pedigree
  • Nephritis, Hereditary
  • Nail-Patella Syndrome
  • Mutation, Missense
  • Male
  • LIM-Homeodomain Proteins
 

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Hall, G., Lane, B., Chryst-Ladd, M., Wu, G., Lin, J.-J., Qin, X., … Gbadegesin, R. (2017). Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation. Sci Rep, 7, 39933. https://doi.org/10.1038/srep39933
Hall, Gentzon, Brandon Lane, Megan Chryst-Ladd, Guanghong Wu, Jen-Jar Lin, XueJun Qin, Elizabeth R. Hauser, and Rasheed Gbadegesin. “Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation.Sci Rep 7 (January 6, 2017): 39933. https://doi.org/10.1038/srep39933.
Hall G, Lane B, Chryst-Ladd M, Wu G, Lin J-J, Qin X, et al. Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation. Sci Rep. 2017 Jan 6;7:39933.
Hall, Gentzon, et al. “Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation.Sci Rep, vol. 7, Jan. 2017, p. 39933. Pubmed, doi:10.1038/srep39933.
Hall G, Lane B, Chryst-Ladd M, Wu G, Lin J-J, Qin X, Hauser ER, Gbadegesin R. Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation. Sci Rep. 2017 Jan 6;7:39933.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

January 6, 2017

Volume

7

Start / End Page

39933

Location

England

Related Subject Headings

  • Young Adult
  • WT1 Proteins
  • Transcription Factors
  • Podocytes
  • Pedigree
  • Nephritis, Hereditary
  • Nail-Patella Syndrome
  • Mutation, Missense
  • Male
  • LIM-Homeodomain Proteins