title: Association Between RET (rs1800860) and GFRA1 (rs45568534, rs8192663, rs181595401, rs7090693, and rs2694770) Variants and Kidney Size in Healthy Newborns.
abstract: 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.
  
  
  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.
authors.affiliation: 1 Department of Clinical and Molecular Biochemistry, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Mariusz
authors.initials: M
authors.lastname: Kaczmarczyk
authors.affiliation: 2 Department of Neonatal Diseases, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Beata
authors.initials: B
authors.lastname: Loniewska
authors.affiliation: 3 Department of Radiology, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Anna
authors.initials: A
authors.lastname: Kuprjanowicz
authors.affiliation: 1 Department of Clinical and Molecular Biochemistry, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Binczak-Kuleta
authors.affiliation: 1 Department of Clinical and Molecular Biochemistry, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Iwona
authors.initials: I
authors.lastname: Goracy
authors.affiliation: 1 Department of Clinical and Molecular Biochemistry, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Ryder
authors.affiliation: 1 Department of Clinical and Molecular Biochemistry, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Olga
authors.initials: O
authors.lastname: Taryma-Lesniak
authors.affiliation: 1 Department of Clinical and Molecular Biochemistry, Pomeranian Medical University , Szczecin, Poland .
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ciechanowicz
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D005260:Female; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D007668:Kidney / Q000000981:diagnostic imaging / Q000254:growth & development*; D008297:Male; D009929:Organ Size / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D051381:Rats; D014463:Ultrasonography
chemical_list: D020413:3' Untranslated Regions; C494987:GFRA1 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
keywords: congenital nephron number; genetic polymorphism; kidney volume; mRNA splicing; nephron endowment