PAX2 mutations in oligomeganephronia

Salomon, Rémi; Tellier, Anne-Lorraine; Attié‐Bitach, Tania; Amiel, Jeanne; Vekemans, Michel; Lyonnet, Stanislas; Dureau, P.; Niaudet, Patrick; Gubler, Marie–Claire; Broyer, M.

doi:10.1046/j.1523-1755.2001.059002457.x

Cited by 110 publications

(95 citation statements)

References 20 publications

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“…It is interesting that reevaluation of some patients with the diagnosis of "oligomeganephronia" also showed some PAX2 mutations (10). In this syndrome, nephron structure seemed normal except that glomeruli were reduced in number and were strikingly hypertrophied (10). This report provided one of the first clues that PAX2 mutations cause a pure nephron deficit.…”

mentioning

confidence: 73%

“…PAX2 belongs to the nine-member family of "paired box" transcription factors and is highly expressed in the UB as it undergoes branching morphogenesis (9). It is interesting that reevaluation of some patients with the diagnosis of "oligomeganephronia" also showed some PAX2 mutations (10). In this syndrome, nephron structure seemed normal except that glomeruli were reduced in number and were strikingly hypertrophied (10).…”

mentioning

confidence: 99%

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Suppression of Ureteric Bud Apoptosis Rescues Nephron Endowment and Adult Renal Function in Pax2 Mutant Mice

Dziarmaga¹,

Eccles²,

Goodyer³

2006

Journal of the American Society of Nephrology

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The molecular mechanisms that set congenital nephron number are unknown. However, humans with modest suboptimal nephron number may be at increased risk for essential hypertension, and those with more severe nephron deficits at birth may develop progressive renal insufficiency. A model of branching morphogenesis during fetal kidney development in which the extent of ureteric bud arborization is dependent on suppression of programmed cell death has been proposed. This study shows that the increased apoptosis and reduced ureteric bud branching of heterozygous Pax2 mutant mice is associated with 40% decrease in nephron number at birth. This leads to postnatal glomerular hypertrophy and long-term renal insufficiency in the absence of glomerulosclerosis. To determine whether restoration of antiapoptotic factors alone is sufficient to rescue the nephron deficit in these mice, a BCL2 transgene that is under the control of the PAX2 promoter was targeted to the ureteric bud. The transgene suppressed programmed cell death in the ureteric bud lineage, increased nephron number to 90% of that of wild-type littermates at birth, and normalized renal function at 1 yr. These observations lend strong support to the hypothesis that factors that control ureteric bud apoptosis are powerful determinants of congenital nephron endowment.

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confidence: 73%

mentioning

confidence: 99%

Suppression of Ureteric Bud Apoptosis Rescues Nephron Endowment and Adult Renal Function in Pax2 Mutant Mice

Dziarmaga¹,

Eccles²,

Goodyer³

2006

Journal of the American Society of Nephrology

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“…3 It has recently been shown to be associated with PAX2 gene mutations as part of the renal-coloboma syndrome. [4][5][6][7] Expression of PAX2 is restricted to cells of astrocytic lineage both during retinal development and in adulthood. Using immunohistochemistry, it has been found that adult retinal cells with the antigenic phenotype present in mature perinatal astrocytes are found only in the region surrounding the optic nerve head, and that astrocyte precursor cells expressing PAX2 are found in a small region surrounding the optic nerve during early development.…”

Section: Aetiologymentioning

confidence: 99%

“…These have been reviewed by Brodsky 11 and include the CHARGE association (coloboma, choanal atresia, congenital heart disease, and multiple other abnormalities), WalkerWarburg syndrome, Goltz focal dermal hypoplasia, Aicardi syndrome, Goldenhar syndrome, and linear sebaceous naevus syndrome. More recently, associations with Dandy Walker malformation 22 and renal coloboma syndrome (with a mutation of PAX2 transcription) [4][5][6][7] have also been described.…”

Section: Associationsmentioning

confidence: 99%

Congenital disorders of the optic nerve: excavations and hypoplasia

Dutton

2004

Eye

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“…In families with the autosomal dominant renal-coloboma syndrome (RCS), more severe renal hypoplasia and ocular colobomas are caused by mutations of a key developmental gene, PAX2 (4). Histopathologic studies of this condition indicate that patients with heterozygous PAX2 mutations have oligomeganephronia-residual nephrons are normally formed and glomeruli exhibit appropriate compensatory hypertrophy, but an absolute nephron deficit causes renal insufficiency (5).…”

mentioning

confidence: 99%

Rescue of Defective Branching Nephrogenesis in Renal-Coloboma Syndrome by the Caspase Inhibitor, Z-VAD-fmk

Clark¹,

Dziarmaga²,

Eccles

et al. 2004

Journal of the American Society of Nephrology

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Abstract. In renal-coloboma syndrome (RCS), null mutations of the PAX2 gene cause renal hypoplasia due to a congenital deficit of nephrons; affected individuals may develop renal insufficiency in childhood. During normal kidney development, PAX2, is expressed at high levels throughout the arborizing ureteric bud (UB); recent observations suggest that one of its key roles is to suppress apoptosis in this collecting duct lineage. The authors hypothesized that increased UB cell apoptosis due to PAX2 haploinsufficiency must directly influence the rate of branching morphogenesis in developing kidney and the number of nephrons that can be formed before birth, when nephrogenesis in humans comes to an end. If so, the authors reasoned that caspase inhibitors might be used to suppress unwanted UB cell apoptosis during kidney development in Pax2 1Neu mutant mice and rescue the genetic UB branching defect. E17.5 kidneys from Pax2 1Neu mutant mice had smaller (Ϫ25%) longitudinal cross-sectional area and 3.5-fold increase in collecting duct cell apoptosis versus wild-type littermates; mutant E13.5 kidney explants allowed to arborize for 50 h in vitro had 18% fewer terminal branches than wild-types. However, exposure to the caspase inhibitor, Z-VAD-fmk (25 M), significantly increased terminal branch number in mutant explants (23%). It also increased branching in wild-type explants, apparently reflecting an effect of Z-VAD-fmk on basal apoptosis induced by ex vivo culture conditions. Similarly, when pregnant mice were injected daily with Z-VAD-fmk (10 g/g weight from E10.5 to E17.5), apoptosis of Pax2 1Neu fetal collecting duct cells was suppressed to 40% of untreated mutants; by E14, terminal branch number was increased to 152% that of untreated litters. These studies support the hypothesis that PAX2 normally optimizes the rate of branching morphogenesis in fetal kidney by suppressing UB apoptosis. Furthermore, it suggests that caspase inhibitors can rescue the branching defect caused by PAX2 mutations.During normal kidney development, interactions between the arborizing ureteric bud (UB) and the metanephric mesenchyme (MM) generate the nephrons of each kidney. This process begins at 5 to 6 wk fetal age, when the UB emerges from the nephric duct, grows laterally into the undifferentiated mesenchyme, and begins to arborize. Each terminal branch of the UB signals adjacent MM cells to form the proximal portion of a nephron, which then fuses to the common collecting system. By about 1 mo before birth, when nephrogenesis comes to a halt, final nephron number has been determined by how many UB branching events have occurred in the intervening period. This crop of fetal nephrons will constitute the individual's nephron endowment for life.Nephron number varies widely from 0.3 to 1.3 million/ kidney among normal humans (1,2). Children born at the lower end of this spectrum may have increased risk of hypertension or susceptibility to acquired renal disease later in life (3). In families with the autosomal dominant renal-coloboma syndrom...

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PAX2 mutations in oligomeganephronia

Abstract: Ocular anomaly and PAX2 mutations should be sought in all patients with OMN.

Cited by 110 publications

References 20 publications

Suppression of Ureteric Bud Apoptosis Rescues Nephron Endowment and Adult Renal Function in Pax2 Mutant Mice

Suppression of Ureteric Bud Apoptosis Rescues Nephron Endowment and Adult Renal Function in Pax2 Mutant Mice

Congenital disorders of the optic nerve: excavations and hypoplasia

Rescue of Defective Branching Nephrogenesis in Renal-Coloboma Syndrome by the Caspase Inhibitor, Z-VAD-fmk

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