Renal Aplasia in Humans Is Associated with RET Mutations

In animal models, kidney formation is known to be controlled by the proteins RET, GDNF, and GFRA1; however, no human studies to date have shown an association between abnormal kidney development and mutation of these genes. We hypothesized that stillborn fetuses with congenital renal agenesis or sev...

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Published in:American journal of human genetics 2008-02, Vol.82 (2), p.344-351
Main Authors: Skinner, Michael A., Safford, Shawn D., Reeves, Justin G., Jackson, Margaret E., Freemerman, Alex J.
Format: Article
Language:English
Subjects:
Base Sequence
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
General aspects. Genetic counseling
Genetics of eukaryotes. Biological and molecular evolution
Glial Cell Line-Derived Neurotrophic Factor - genetics
Humans
Kidney - abnormalities
Kidney Diseases - genetics
Medical genetics
Medical sciences
Molecular and cellular biology
Molecular Sequence Data
Mutagenesis, Site-Directed
Mutation - genetics
Phosphorylation
Plasmids - genetics
Proto-Oncogene Proteins c-ret - genetics
Proto-Oncogene Proteins c-ret - metabolism
Sequence Analysis, DNA
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Summary:In animal models, kidney formation is known to be controlled by the proteins RET, GDNF, and GFRA1; however, no human studies to date have shown an association between abnormal kidney development and mutation of these genes. We hypothesized that stillborn fetuses with congenital renal agenesis or severe dysplasia would possess mutations in RET, GDNF, or GFRA1. We assayed for mutations in these genes in 33 stillborn fetuses that had bilateral or unilateral renal agenesis (29 subjects) or severe congenital renal dysplasia (4 subjects). Mutations in RET were found in 7 of 19 fetuses with bilateral renal agenesis (37%) and 2 of 10 fetuses (20%) with unilateral agenesis. In two fetuses, there were two different RET mutations found, and a total of ten different sequence variations were identified. We also investigated whether these mutations affected RET activation; in each case, RET phosphorylation was either absent or constitutively activated. A GNDF mutation was identified in only one fetus with unilateral agenesis; this subject also had two RET mutations. No GFRA1 mutations were seen in any fetuses. These data suggest that in humans, mutations in RET and GDNF may contribute significantly to abnormal kidney development.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2007.10.008