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

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

Author information

1
Duke Molecular Physiology Institute, Durham, NC, United States.
2
Division of Nephrology, Duke University Medical Center, Durham, NC, United States.
3
Department of Pediatrics, Duke University Medical Center, Durham, NC, United States.
4
Department of Pediatrics, Wake Forest Baptist Medical Center, Winston Salem, NC, United States.

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.

PMID:
28059119
PMCID:
PMC5216339
DOI:
10.1038/srep39933
[Indexed for MEDLINE]
Free PMC Article

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