Papillorenal Syndrome-Causing Missense Mutations in PAX2/Pax2 Result in Hypomorphic Alleles in Mouse and Human

Alur, Ramakrishna P.; Vijayasarathy, Camasamudram; Brown, Jacob D.; Mehtani, Mohit; Onojafe, Ighovie F.; Sergeev, Yuri V.; Elangovan, B.; Jones, MaryPat; Tang, Ke; Liu, Haiquan; Xia, Chun-hong; Gong, Xiaohua; Brooks, Brian P.

doi:10.1371/journal.pgen.1000870

Cited by 23 publications

(15 citation statements)

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“…42 In both mice and zebrafish, homozygous mutations in Pax2/pax2a result in failed optic fissure closure and a defect resembling chorioretinal coloboma, whereas studies in Pax2 haploinsufficient mice demonstrate that the optic fissure fails to extend into the optic stalk with a dysplasic optic disc. 43,44 This suggests that in the presence of a PAX2 mutation, the observed optic malformations result from optic fissure defects and supports the notion that the observed abnormalities in RCS should be considered in the continuum of malformations described as coloboma.…”

Section: Animal Modelssupporting

confidence: 66%

Renal coloboma syndrome

Schimmenti

2011

Eur J Hum Genet

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In association withRenal coloboma syndrome Renal coloboma syndrome (RCS), also called papillorenal syndrome, is an autosomal dominant condition characterized by optic nerve dysplasia and renal hypodysplasia. The eye anomalies consist of a wide and sometimes excavated dysplastic optic disc with the emergence of the retinal vessels from the periphery of the disc, frequently called optic nerve coloboma or morning glory anomaly. Associated findings may include a small corneal diameter, retinal coloboma, scleral staphyloma, optic nerve cyst and pigmentary macular dysplasia. The kidney abnormalities consist of small and abnormally formed kidneys known as renal hypodysplasia. Histologically, kidneys exhibit fewer than the normal number of glomeruli and these glomeruli are enlarged, a finding called oligomeganephronia. Consequences of the ocular malformations include decreased visual acuity and retinal detachment. Consequences of the renal hypodysplasia include hypertension, proteinuria and renal insufficiency that frequently progresses to end-stage kidney disease. High frequency hearing loss has been reported. Autosomal dominant mutations in PAX2 can be identified in nearly half of all patients with clinical findings suggestive of RCS, however, the majority of published cases have mutations in PAX2, thus biasing the known information about the phenotype.

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Section: Animal Modelssupporting

confidence: 66%

Renal coloboma syndrome

Schimmenti

2011

Eur J Hum Genet

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“…Further support of PAX2 gene dosage being critical for normal development was obtained in mouse models where knockout of or nonsense mutations in the PAX2 gene led to a phenotype analogous to PRS. [30][31][32] We provide evidence that missense mutations can lead to disease through loss of function but by diverse mechanism(s) as well, which could have implications for individualizing drug therapy. 27 …”

Section: Discussionmentioning

confidence: 99%

Mutations in PAX2 Associate with Adult-Onset FSGS

Barua

Stellacci²,

Stella

et al. 2014

Journal of the American Society of Nephrology

103

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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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“…Finally, mutations in Wnt signaling genes Lrp6, frizzled 5 (Fzd5) and β-catenin (Ctnnb1), which are known to regulate the dorsal-ventral patterning of optic vesicle and the specification of the RPE, all cause ocular coloboma (Liu et al, 2007;Liu and Nathans, 2008;Zhou et al, 2008;Fujimura et al, 2009;Westenskow et al, 2009). Many of these coloboma mutants, as well as human patients, exhibit dysregulation of Pax2, a key homeodomain protein required for the closure but not the initiation of the optic fissure (Torres et al, 1996;Alur et al, 2010;Cross et al, 2011). In addition, mutations in ocular transcription factors, e.g.…”

Section: Introductionmentioning

confidence: 99%

Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma

Cai

Tao

et al. 2013

Development

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SUMMARYFGF signaling plays a pivotal role in eye development. Previous studies using in vitro chick models and systemic zebrafish mutants have suggested that FGF signaling is required for the patterning and specification of the optic vesicle, but due to a lack of genetic models, its role in mammalian retinal development remains elusive. In this study, we show that specific deletion of Fgfr1 and Fgfr2 in the optic vesicle disrupts ERK signaling, which results in optic disc and nerve dysgenesis and, ultimately, ocular coloboma. Defective FGF signaling does not abrogate Shh or BMP signaling, nor does it affect axial patterning of the optic vesicle. Instead, FGF signaling regulates Mitf and Pax2 in coordinating the closure of the optic fissure and optic disc specification, which is necessary for the outgrowth of the optic nerve. Genetic evidence further supports that the formation of an Frs2α-Shp2 complex and its recruitment to FGF receptors are crucial for downstream ERK signaling in this process, whereas constitutively active Ras signaling can rescue ocular coloboma in the FGF signaling mutants. Our results thus reveal a previously unappreciated role of FGF-Frs2α-Shp2-Ras-ERK signaling axis in preventing ocular coloboma. These findings suggest that components of FGF signaling pathway may be novel targets in the diagnosis of and the therapeutic interventions for congenital ocular anomalies.

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Papillorenal Syndrome-Causing Missense Mutations in PAX2/Pax2 Result in Hypomorphic Alleles in Mouse and Human

Cited by 23 publications

References 50 publications

Renal coloboma syndrome

Renal coloboma syndrome

Mutations in PAX2 Associate with Adult-Onset FSGS

Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma

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