The pathomechanism leading to nail-patella syndrome depends on the nature of the mutation

Lisa Lucke

University Regensburg,Germany

Posters & Accepted Abstracts: J Transplant Technol Res

Abstract :

Nail-patella syndrome (NPS) is an autosomal-dominant genetic disorder characterized by malformed fingernails and hypoplastic kneecaps. Approximately 40% of NPS patients develop a nephropathy caused by malfunctioning podocytes. Mutations in the gene LMX1B which encodes a transcription factor of the LIM-homeodomain family are known to be the cause of NPS. The pathomechanism underlying NPS is still unknown. Notably, only homozygous Lmx1b knock-out mice develop symptoms resembling those in NPS patients. We therefore hypothesized that patients suffer from missense mutations which confer a gain-of-function or a dominant-negative effect. To identify possible molecular pathomechanisms of NPS, knock-in mice were established with point mutations either in the first (H54L) or the second (C95F) LIM domain such as those described in patients. Heterozygous Lmx1b knock-in mice showed no NPS phenotype whereas homozygous knock-in mice displayed a reduced number of filtration slits in podocytes, similar to that of conventional Lmx1b knock-out animals. The presence of the mutated Lmx1b mRNA was confirmed but the protein was not detectable in podocytes. Detailed analyses of LMX1B mutants showed a reduced half-life of the mutant proteins in comparison to wild-type LMX1B. Another mutant LMX1B protein with a mutation in the homeodomain, V265D, showed a prolonged half-life compared to the wild-type protein. Due to protein instability, the knock-in mutations H54L and C95F lead to a loss of function in knock-in mice. As previously described, the mutation V265D within the homeodomain causes a dominant-negative effect. This suggests that different NPS mutations can lead to different pathomechanisms requiring distinct therapeutical approaches.

Biography :

Lisa Lucke has completed her studies in biology at the University of Regensburg. In particular, she pursued her Master studies in a biotechnical company producing and testing antigens for T-cell diagnostics. Since 2016, she is working on her PhD at the chair of Prof. Dr. Ralph Witzgall, University of Regensburg. Her research area is based on a genetic disease, called nail-patella syndrome. Her topic deals with the analysis of different mutations in the transcription factor LMX1B that could lead to different pathomechanisms of nail-patela syndrome.

E-mail: lisa.lucke@ur.de