title: Mutations in PAX2 associate with adult-onset FSGS.
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.
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
authors.forename: Moumita
authors.initials: M
authors.lastname: Barua
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy;
authors.forename: Emilia
authors.initials: E
authors.lastname: Stellacci
authors.affiliation: Department of Chemical Science and Technology, University of Rome Tor Vergata, Rome, Italy;
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Stella
authors.affiliation: Department of Pathology, and.
authors.forename: Astrid
authors.initials: A
authors.lastname: Weins
authors.affiliation: 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.
authors.forename: Giulio
authors.initials: G
authors.lastname: Genovese
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy;
authors.forename: Valentina
authors.initials: V
authors.lastname: Muto
authors.affiliation: Department of Experimental Medicine, University "La Sapienza," Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.affiliation: 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;
authors.forename: Hakan R
authors.initials: HR
authors.lastname: Toka
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
authors.forename: Victoria T
authors.initials: VT
authors.lastname: Charoonratana
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, National Institute of Health, Rome, Italy; mpollak@bidmc.harvard.edu marco.tartaglia@iss.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
authors.forename: Martin R
authors.initials: MR
authors.lastname: Pollak
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D015331:Cohort Studies; D003198:Computer Simulation; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D051762:PAX2 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D055672:Static Electricity; D014564:Urogenital Abnormalities; D014718:Vesico-Ureteral Reflux / Q000235:genetics; D055815:Young Adult
chemical_list: D051762:PAX2 Transcription Factor; C497318:PAX2 protein, human