A common RET variant Is associated with reduced newborn kidney size and function

Zhao Zhang, Jackie Quinlan, Wendy E Hoy, Michael D Hughson, Mathieu Lemire, Thomas Hudson, Pierre-Alain Hueber, Alice Benjamin, Anne Roy, Elena Pascuet, Meigan Goodyer, Chandhana Raju, Fiona Houghton, John Frederick Bertram, Paul Goodyer

Research output: Contribution to journalArticleResearchpeer-review

107 Citations (Scopus)


Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10 smaller and cord blood cystatin C levels 9 higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.
Original languageEnglish
Pages (from-to)2027 - 2034
Number of pages8
JournalJournal of the American Society of Nephrology
Issue number10
Publication statusPublished - 2008

Cite this