Abstract
Nail Patella syndrome (NPS) is a rare autosomal dominant disease characterized by varying degrees of patella, nail, and elbows dysplasia and also ocular and renal congenital abnormalities. The renal involvement, ranging from hematuria and proteinuria to end-stage renal disease, is present in 22–60% of NPS cases. Heterozygous variants in LMX1B are known to be responsible of NPS and it has been hypothesized that the variable expressivity is due to the interaction of LMX1B with other developmental genes. We reported a case of co-presence of LMX1B and PAX2 variants in a child with extrarenal manifestation of NPS and end-stage renal disease but congenital bilateral renal hypodysplasia and vesicoureteral reflux. The LMX1B variant was de novo, whereas the PAX2 variant was inherited from the mother that had bilateral renal hypoplasia although in presence of only a mild chronic kidney disease. The molecular interaction between LMX1B and PAX2 has been already reported in vitro and this finding suggest that the worst renal NPS phenotype of our patient could be due to the defective expression of these two genes during nephrogenesis. In conclusion, our finding suggests that PAX2 may act as modifier gene in Nail Patella phenotype.
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ghoumid J, Petit F, Holder-Espinasse M, et al. Nail–Patella syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity. Eur J Hum Genet. 2016;24:44–50.
Boyer O, Woerner S, Yang F, et al. LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol. 2013;24:1216–22.
Edwards N, Rice SJ, Raman S, et al. A novel LMX1B mutation in a family with end-stage renal disease of “unknown cause”. Clin Kidney J. 2014;8:113–9.
Marini M, Giacopelli F, Seri M, Ravazzolo R. Interaction of the LMX1B and PAX2 gene products suggests possible molecular basis of differential phenotypes in Nail-Patella syndrome. Eur J Hum Genet. 2005;13:789–92.
Dressler GR. Patterning and early cell lineage decisions in the developing kidney: the role of Pax genes. Pediatr Nephrol. 2011;26:1387–94.
Negrisolo S, Benetti E, Centi S, et al. PAX2 gene mutations in pediatric and young adult transplant recipients: kidney and urinary tract malformations without ocular anomalies. Clin Genet. 2011;80:581–5.
Barua M, Stellacci E, Stella L, et al. Mutations in PAX2 associate with adult-onset FSGS. J Am Soc Nephrol. 2014;25:1942–53.
Dunston JA, Hamlington JD, Zaveri J, et al. The human LMX1B gene: transcription unit, promoter, and pathogenic mutations. Genomics. 2004;84:565–76.
Schwarz JM, Cooper DN, Schuelke M, Seelow D. MutationTaster2: mutation prediction for the deep-sequencing age. Nat Meth. 2014;11:361–2.
Lambert C, Léonard N, De Bolle X, Depiereux E. ESyPred3D: prediction of proteins 3D structures. Bioinformatics. 2002;18:1250–6.
Makarewicz T, Kaźmierkiewicz R. Improvements in GROMACS plugin for PyMOL including implicit solvent simulations and displaying results of PCA analysis. J Mol Model. 2016;22:109.
Nicolaou N, Renkema KY, EMHF Bongers, Giles RH, NVAM Knoers. Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol. 2015;11:720–31.
Sweeney E, Hoover-Fong JE, McIntosh I. Nail-Patella syndrome. GeneReviews®. 2003. https://www.ncbi.nlm.nih.gov/books/NBK1132/.
Bergmann C, von Bothmer J, Ortiz Brüchle N, et al. Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J Am Soc Nephrol. 2011;22:2047–56.
Elumalai R, Periasamy S, Ramanathan G, Lakkakula BV, Soundararajan P. Journal of Renal Injury Prevention Role of endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism on the progression of renal disease in autosomal dominant polycystic kidney disease. J Renal Inj Prev. 2014;3:69–73.
Stokman MF, Renkema KY, Giles RH, Schaefer F, NVAM Knoers, van Eerde AM. The expanding phenotypic spectra of kidney diseases: insights from genetic studies. Nat Rev Nephrol. 2016;12:472–83.
Chatterjee R, Ramos E, Hoffman M, et al. Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum Genet. 2012;131:1725–38.
Renkema KY, Stokman MF, Giles RH. Knoers NVAM: next-generation sequencing for research and diagnostics in kidney disease. Nat Rev Nephrol. 2014;10:433–44.
Acknowledgements
The authors gratefully acknowledge the participation of Dr. Lina Artifoni and all clinicians of Padua Pediatric Nephrology, Dialysis and Transplant Unit, and Dr. Piera De Gaspari of Padua for the critical review.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Negrisolo, S., Carraro, A., Fregonese, G. et al. Could the interaction between LMX1B and PAX2 influence the severity of renal symptoms?. Eur J Hum Genet 26, 1708–1712 (2018). https://doi.org/10.1038/s41431-018-0213-4
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41431-018-0213-4
This article is cited by
-
UDA-seq: universal droplet microfluidics-based combinatorial indexing for massive-scale multimodal single-cell sequencing
Nature Methods (2025)
-
Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis
Pediatric Nephrology (2020)
