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.

Hereditary Podocytopathies in Adults: The Next Generation

“…PAX2 mutations were also identified by exome sequencing in seven families with AD FSGS, mostly diagnosed in the second to fourth decades of life [60] . Heterozygous mutations of PAX2 were thus far known to cause congenital anomalies of the kidney and urinary tract (CAKUT), as well as papillorenal syndrome (renal hypodysplasia and optic nerve coloboma).…”

“…Heterozygous mutations of PAX2 were thus far known to cause congenital anomalies of the kidney and urinary tract (CAKUT), as well as papillorenal syndrome (renal hypodysplasia and optic nerve coloboma). Mutated patients may have either normal kidney ultrasound or echoic or small kidneys, dilated renal pelvis or calices [60] . Most patients do not have any extrarenal symptom.…”

“…PAX2 is a transcription factor expressed during the development of the kidney as well as the otic and optic vesicles and the hindbrain. PAX2 mutations could result in FSGS secondary to nephron loss, but through dysregulation of target genes such as the transcription factor WT1 [60] .…”

Evaluation of Genetic Renal Diseases in Potential Living Kidney Donors

“…The availability of genetic testing demonstrates that there is some overlap between genes that cause the three clinical entities of CNS, childhood-onset SRNS, and later-onset, usually autosomal-dominant, FSGS. Furthermore, PAX2 mutations can also cause papillorenal syndrome, which is a developmental disorder that includes congenital anomalies of the kidney or urinary tract and retinal or optic nerve coloboma [42,43]. In addition, there are syndromic forms of SRNS, for example, Denys Drash and Frasier syndrome caused by WT1 mutations and nail-patella syndrome caused by LMX1B mutations.…”

Three Novel Heterozygous<b><i> COL4A4</i></b> Mutations Result in Three Different Collagen Type IV Kidney Disease Phenotypes

“…It is reported that TBMN, characterized by persistent glomerular hematuria, minimal proteinuria and normal renal function, is caused by heterozygous mutations in the COL4A3 or COL4A4 genes in about 40% of the patients [Papazachariou et al, 2014]. As a pathological phenotype, the causative genes of FSGS have been consistently investigated [Barua et al, 2014;Huynh Cong et al, 2014]. Recently, it has been shown that familial FSGS can also be explained by heterozygous mutations in the COL4A3 or COL4A4 genes [Gast et al, 2016;Wu et al, 2016].…”