Mutations in PAX2 associate with adult-onset FSGS

J Am Soc Nephrol. 2014 Sep;25(9):1942-53. doi: 10.1681/ASN.2013070686.

Moumita Barua ¹, Emilia Stellacci ², Lorenzo Stella ³, Astrid Weins ⁴, Giulio Genovese ⁵, Valentina Muto ², Viviana Caputo ⁶, Hakan R Toka ⁷, Victoria T Charoonratana ¹, Marco Tartaglia ⁸, Martin R Pollak ¹

Affiliations

1 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
2 Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy;
3 Department of Chemical Science and Technology, University of Rome Tor Vergata, Rome, Italy;
4 Department of Pathology, and.
5 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Stanley Center for Psychiatric Research, Cambridge, Massachusetts; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Genetics, Harvard Medical School, Boston, Massachusetts; and.
6 Department of Experimental Medicine, University "La Sapienza," Rome, Italy.
7 Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Division of Nephrology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
8 Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy; mpollak@bidmc.harvard.edu marco.tartaglia@iss.it.

PMID: 24676634 DOI: 10.1681/ASN.2013070686

Abstract

FSGS is characterized by the presence of partial sclerosis of some but not all glomeruli. Studies of familial FSGS have been instrumental in identifying podocytes as critical elements in maintaining glomerular function, but underlying mutations have not been identified for all forms of this genetically heterogeneous condition. Here, exome Sequencing in members of an index family with dominant FSGS revealed a nonconservative, disease-segregating variant in the PAX2 transcription factor gene. Sequencing in probands of a familial FSGS cohort revealed seven rare and private heterozygous single nucleotide substitutions (4% of individuals). Further Sequencing revealed seven private missense variants (8%) in a cohort of individuals with congenital abnormalities of the kidney and urinary tract. As predicted by in silico structural modeling analyses, in vitro functional studies documented that several of the FSGS-associated PAX2 mutations perturb protein function by affecting proper binding to DNA and transactivation activity or by altering the interaction of PAX2 with repressor proteins, resulting in enhanced repressor activity. Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations. These results expand the phenotypic spectrum associated with PAX2 mutations, which have been shown to lead to congenital abnormalities of the kidney and urinary tract as part of papillorenal syndrome. Moreover, these results indicate PAX2 mutations can cause disease through haploinsufficiency and dominant negative effects, which could have implications for tailoring individualized drug therapy in the future.

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