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A Common RET Variant Is Associated with Reduced Newborn Kidney Size and Function

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

^* McGill University Health Centre Research Institute, McGill University and Génome Québec Innovation Centre, and Departments of ^|| Obstetrics and Gynecology and ^¶ Radiology, McGill University, Montreal, Québec, Canada; Centre for Chronic Diseases, University of Queensland, Brisbane, and ^** Department of Anatomy and Developmental Biology, Monash University, Victoria, Australia; and University of Mississippi Medical Center, Jackson, Mississippi

Correspondence: Dr. Paul Goodyer, 4060 Saint Catherine West, PT-413, Montreal Quebec, Canada H3Z 2Z3. Phone: 514-412-4461; Fax: 514-412-4478; E-mail: paul.goodyer{at}mcgill.ca

Received for publication October 12, 2007. Accepted for publication April 18, 2008.

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.

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J. Am. Soc. Nephrol. 2008 19: A6. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673