A Common Variant of the PAX2 Gene Is Associated with Reduced Newborn Kidney Size

Department of Obstetrics and Gynecology, McGill University, Montréal, Quebec, Canada
Journal of the American Society of Nephrology (Impact Factor: 9.34). 07/2007; 18(6):1915-21. DOI: 10.1681/ASN.2006101107
Source: PubMed


Congenital nephron number ranges widely in the human population. Suboptimal nephron number may be associated with increased risk for essential hypertension and susceptibility to renal injury, but the factors that set nephron number during kidney development are unknown. In renal-coloboma syndrome, renal hypoplasia and reduced nephron number are due to heterozygous mutations of the PAX2 gene. This study tested for an association between a common haplotype of the PAX2 gene and subtle renal hypoplasia in normal newborns. A PAX2 haplotype was identified to occur in 18.5% of the newborn cohort, which was significantly associated with a 10% reduction in newborn kidney volume adjusted for body surface area. This haplotype was also associated with reduced allele-specific PAX2 mRNA level in a human renal cell carcinoma cell line. Subtle renal hypoplasia in normal newborns may be partially due to a common variant of the PAX2 gene that reduces mRNA expression during kidney development.

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    • "Some authors believe that PAX2 acts by regulating the interaction between the UB and the metanephric blastema. This interaction seems to be one of the critical phases for the occurrence of the UB branching (Dziarmaga et al., 2006; Quinlan et al., 2007). It was suggested that PAX2 activates intermediate factors that transiently lead UB cells to avoid programmed cell death during branching morphogenesis in fetal kidney by suppressing apoptosis in renal collecting ducts (Torban et al., 2000). "
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    ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a broad range of disorders that result from abnormalities of the urinary collecting system, abnormal embryonic migration of the kidneys, or abnormal renal parenchyma development. These disorders are commonly found in humans, accounting for 20-30% of all genetic malformations diagnosed during the prenatal period. It has been estimated that CAKUT are responsible for 30-50% of all children with chronic renal disease worldwide and that some anomalies can predispose to adult-onset diseases, such as hypertension. Currently, there is much speculation regarding the pathogenesis of CAKUT. Common genetic background with variable penetrance plays a role in the development of the wide spectrum of CAKUT phenotypes. This review aims to summarize the possible mechanisms by which genes responsible for kidney and urinary tract morphogenesis might be implicated in the pathogenesis of CAKUT. Birth Defects Research (Part C), 2014. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc.
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    • "Animal models evaluating the effects of a low-protein diet during pregnancy have shown that offsprings with reduced number of glomeruli who develop hypertension in adulthood have altered expression of genes controlling metanephric organogenesis [35, 55, 56, 77, 83, 98–102]. The critical role of mutations in genes that direct metanephric organogenesis in developmental programming of renal dysfunction and blood pressure is supported by observations that polymorphisms in paired box 2 (Pax-2) or Ret, genes shown to be critical for normal kidney development in animal models, are associated with reduced renal volume in humans and may therefore associate with a reduced number of nephrons [103, 104]. Exposure to maternal low-protein diet in utero in the rat causes hypertension associated with microvascular rarefaction (reduced density of arterioles and capillaries) and decreased angiogenesis [105, 106]. "
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    • "Massively parallel exon sequencing of 30 candidate genes in pooled DNA from children with unilateral renal agenesis, renal hypodysplasia, or VUR in the United States identified novel mutations in 4 genes (Ret, BMP4, FRAS1, and FREM2) in 17% of cases [21]. Pax-2, but not its downstream target gene, GDNF, polymorphism (a variation in the DNA sequence at a given locus that is too common to be due merely to new mutation) is associated with reduced kidney size in neonates [34, 35]. The differential effects of Pax2 and GDNF polymorphism on CAKUT phenotype may be due, in part, to unidentified cell-specific cofactors that regulate gene expression. "
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