NDT Advance Access originally published online on December 8, 2007
Nephrology Dialysis Transplantation 2008 23(2):777-779; doi:10.1093/ndt/gfm685
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Missense mutations in EYA1 and TCF2 are a rare cause of urinary tract malformations
E-mail: fhilde{at}umich.edu
Sir,
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 
0.5% of pregnancies; they cover a range of structural and often functional malformations resulting from defects in development of the kidney and/or lower urinary tract [1]. Renal development is a complex process involving multiple transcription factors, which direct the temporal and spatial expression of specific genes required for kidney organogenesis [2]. Defects at any of the critical steps involved in this process can result in a malformed kidney. To determine the contribution of mutations in EYA1 and TCF2 to CAKUT, we screened a worldwide cohort of 172 patients for mutations in both genes.
This study was approved by the Institutional Review Board of the University of Michigan Medical School (2004-0322, HUM00003330). All exons of both genes were screened, using multiplex capillary heteroduplex analysis (MCHA) [3]. Two hundred ethnically matched control chromosomes were also screened using MCHA. Our cohort of CAKUT patients was defined by one or more of the following diagnoses: vesico-ureteric reflux (VUR), duplication of the collecting system, ureteropelvic junction obstruction (UPJO), renal agenesis, multicystic dysplastic kidney (MCDK) and ectopic kidney (Table 1). The median age of patients was 16 years (range 2–68 years). The majority of patients was European (80.2%) with the remainder being either Middle Eastern (15.7%), Asian (3.5%) or African (0.6%).
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Most cases were non-syndromic, as assessed by completion of a health questionnaire (www.renalgenes.org). Two patients met the diagnostic criteria for VACTERL association, a ‘non-random’ association of congenital anomalies [4].
We identified a novel heterozygous missense mutation in exon 7 of EYA1, P216L, in patient A1522 II-1 with a unilateral UPJO and reduced renal function (creatinine clearance—56 mg/dl (Figure 1)). The patient shows no additional signs of Brachio-Oto-Renal (BOR) Syndrome such as deafness or branchial arch defects, suggesting that the P216L mutation, in this patient, manifests as an isolated renal phenotype. Samples from parents, neither of whom has a urinary tract malformation, were not available for testing.
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We identified a single missense mutation in exon 1 of TCF2, V61G, in individual A611 II-1 from our cohort (Figure 1). The patient has VACTERL association with a phenotype of unilateral multicystic dysplastic kidney with normal function (creatinine clearance—0.3 mg/dl), ventricular septal defect, anal atresia and tracheo-esophageal fistula. The mutation was not inherited from the mother who has obesity, hypertension and hyperglycaemia. The V61G mutation was previously reported in an adult patient with renal agenesis [5]. As agenesis can result from either a failure of the ureteric bud to make contact with the metanephric mesenchyme during development, or from regression of a multicystic dysplastic kidney, it is possible that this mutation manifests as the same phenotype in both patients.
These results indicate that mutations in EYA1 and TCF2 rarely result in an isolated CAKUT phenotype.
1Departments of Pediatrics
and Human Genetics, University of
Michigan, Ann Arbor, MI, USA
2Department of Pediatric
Nephrology, University
Children's Hospital, Skopje,
Macedonia
3Department of Surgery,
Division of Urology,
Kuwait University, Kuwait
4Institute of Mother and
Child Healthcare, Belgrade,
Republic of Serbia
5Department of Pediatrics,
Ludwig-Maximilians-Universitat
München, Munich, Germany
6Department of Pediatrics,
University of Freiburg,
Freiburg, Germany
Acknowledgements
We thank the patients and their families for their contribution. We also thank Dr Jovana Putnik and Dr Natasa Stajic for their involvement in the ascertainment of patient samples. This work was supported by a grant from the National Institutes of Health to FH (R01-DK045345-01).
Conflict of interest statement. None declared.
Notes
See http://ndtplus.oxfordjournals.org/
References
- Pope JC IV, Brock JW III, Adams MC, et al. How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT. J Am Soc Nephrol (1999) 10:2018–2028.
[Free Full Text] - Bouchard M. Transcriptional control of kidney development. Differentiation (2004) 72:295–306.[CrossRef][Web of Science][Medline]
- Hoskins BE, Thorn A, Scambler PJ, et al. Evaluation of multiplex capillary heteroduplex analysis: a rapid and sensitive mutation screening technique. Hum Mutat (2003) 22:151–157.[CrossRef][Web of Science][Medline]
- Shaw-Smith C. Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J Med Genet (2006) 43:545–554.
[Abstract/Free Full Text] - Edghill EL, Bingham C, Ellard S, et al. Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet (2006) 43:84–90.
[Abstract/Free Full Text]
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