BACKGROUND: Abnormal congenital nephron number has been implicated in the pathogenesis of hypertension and renal disease. The RET receptor complex propagates signals essential for nephrogenesis and the RET c.1296G>A polymorphism, leading to aberrant splicing of exon 7, is associated with reduced kidney volume, a surrogate for nephron endowment. The glial cell-derived neurotrophic factor (GDNF) family receptor alpha 1 (GFRA1) is a component of the RET receptor complex, and three alternatively spliced GFRA1 transcripts (with or without exon 5) have been identified. In rats, exclusion of exon 5 results in stronger GDNF binding affinity and RET activation. The aims of this study were to investigate further the relationship between RET c.1296G>A and kidney volume, and also to investigate the association between the GFRA1 polymorphisms near and within the alternatively spliced exon 5, as well as the functional 5'-UTR c.-193C>G with kidney volume. MATERIALS AND METHODS: The study included 188 healthy full-term newborns. Genotyping of the RET (NM_020975.4:c.1296G>A, rs1800860) and GFRA1 (NM_005264.5:c.-193C>G, rs45568534; c.419-87A>G, rs8192663; c.429G>A, rs181595401; c.433+127A>G, rs7090693; c.433+245A>G, rs2694770) polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism, minisequencing, or sequencing. Total kidney volume (TKV) was determined by ultrasound and normalized to body surface area (TKV/BSA). Both marker-by-marker and haplotype-based methods were used to test for associations between polymorphisms and TKV/BSA. RESULTS: TKV/BSA in RET c.1296A allele carriers was significantly lower compared with GG homozygotes (103 ± 23 vs. 110 ± 19 mL/m2, p = 0.034). c.429G>A was invariant in our sample. There was no association between any of the GFRA1 polymorphisms and renal volume. CONCLUSIONS: RET c.1296A may be a common susceptibility allele for nephron underdosing-related diseases. The 5'-UTR and intronic variants near exon 5 of GFRA1 are not associated with nephron endowment.
BACKGROUND:Abnormal congenital nephron number has been implicated in the pathogenesis of hypertension and renal disease. The RET receptor complex propagates signals essential for nephrogenesis and the RET c.1296G>A polymorphism, leading to aberrant splicing of exon 7, is associated with reduced kidney volume, a surrogate for nephron endowment. The glial cell-derived neurotrophic factor (GDNF) family receptor alpha 1 (GFRA1) is a component of the RET receptor complex, and three alternatively spliced GFRA1 transcripts (with or without exon 5) have been identified. In rats, exclusion of exon 5 results in stronger GDNF binding affinity and RET activation. The aims of this study were to investigate further the relationship between RET c.1296G>A and kidney volume, and also to investigate the association between the GFRA1 polymorphisms near and within the alternatively spliced exon 5, as well as the functional 5'-UTR c.-193C>G with kidney volume. MATERIALS AND METHODS: The study included 188 healthy full-term newborns. Genotyping of the RET (NM_020975.4:c.1296G>A, rs1800860) and GFRA1 (NM_005264.5:c.-193C>G, rs45568534; c.419-87A>G, rs8192663; c.429G>A, rs181595401; c.433+127A>G, rs7090693; c.433+245A>G, rs2694770) polymorphisms was performed using polymerase chain reaction-restriction fragment length polymorphism, minisequencing, or sequencing. Total kidney volume (TKV) was determined by ultrasound and normalized to body surface area (TKV/BSA). Both marker-by-marker and haplotype-based methods were used to test for associations between polymorphisms and TKV/BSA. RESULTS: TKV/BSA in RET c.1296A allele carriers was significantly lower compared with GG homozygotes (103 ± 23 vs. 110 ± 19 mL/m2, p = 0.034). c.429G>A was invariant in our sample. There was no association between any of the GFRA1 polymorphisms and renal volume. CONCLUSIONS:RET c.1296A may be a common susceptibility allele for nephron underdosing-related diseases. The 5'-UTR and intronic variants near exon 5 of GFRA1 are not associated with nephron endowment.