Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 2, 344-351, 31 January 2008
doi:10.1016/j.ajhg.2007.10.008
Article
Renal Aplasia in Humans Is Associated with RET Mutations
Michael A. Skinner1, 
, 
, Shawn D. Safford2, Justin G. Reeves3, Margaret E. Jackson4 and Alex J. Freemerman4
1 Division of Pediatric Surgery, Children's Medical Center of Dallas and University of Texas Southwestern Medical School, Dallas, TX 75235, USA
2 Pediatric General and Thoracic Surgery, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
3 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA
4 Division of Pediatric Surgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
Corresponding authorAbstract
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.
Article Information
PubMed
Related Articles
- Mutations of the RET-GDNF Signaling Pathway in Ondine's Curs...Mutations of the RET-GDNF Signaling Pathway in Ondine's Curse
The American Journal of Human Genetics, Volume 62, Issue 3, 1 March 1998, Pages 715-717
Jeanne Amiel, Rémi Salomon, Tania Attié, Anna Pelet, Ha Trang, Mustapha Mokhtari, Claude Gaultier, Arnold Munnich and Stanislas Lyonnet
| - Double Heterozygosity for a RET Substitution Interfering wit...Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease
The American Journal of Human Genetics, Volume 64, Issue 4, 1 April 1999, Pages 1216-1221
Alberto Auricchio, Paola Griseri, Maria Luisa Carpentieri, Nicola Betsos, Annamaria Staiano, Arturo Tozzi, Manuela Priolo, Helen Thompson, Renata Bocciardi, Giovanni Romeo, Andrea Ballabio and Isabella Ceccherini
| - Gdnf Haploinsufficiency Causes Hirschsprung-Like Intestinal ...Gdnf Haploinsufficiency Causes Hirschsprung-Like Intestinal Obstruction and Early-Onset Lethality in Mice
The American Journal of Human Genetics, Volume 70, Issue 2, 1 February 2002, Pages 435-447
Liya Shen, José G. Pichel, Thomas Mayeli, Hannu Sariola, Bai Lu and Heiner Westphal
AbstractHirschsprung disease (HSCR) is a common congenital disorder that results in intestinal obstruction and lethality, as a result of defective innervation of the gastrointestinal (GI) tract. Despite its congenital origin, the molecular etiology of HSCR remains elusive for >70% of patients. Although mutations in the c-RET receptor gene are frequently detected in patients with HSCR, mutations in the gene encoding its ligand (glial cell line–derived neurotrophic factor [GDNF]), are rarely found. In an effort to establish a possible link between human HSCR and mutations affecting the Gdnf locus, we studied a large population of mice heterozygous for a Gdnf null mutation. This Gdnf+/− mutant cohort recapitulates complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of one functioning Gdnf allele causes a spectrum of defects in gastrointestinal motility and predisposes the mutant mice to HSCR-like phenotypes. As many as one in five Gdnf+/− mutant mice die shortly after birth. Using a transgenic marking strategy, we identified hypoganglionosis of the gastrointestinal tract as a developmental defect that renders the mutant mice susceptible to clinical symptoms of HSCR. Our findings offer a plausible way to link an array of seemingly disparate features characteristic of a complex disease to a much more narrowly defined genetic cause. These findings may have general implications for the genetic analysis of cause and effect in complex human diseases.
Abstract | | - …more
