1. ¹Department of Pediatric Nephrology of the University Children's Hospital, University of Cologne, Cologne, Germany
2. ²Department of Human Genetics, University of Cologne, Cologne, Germany
3. ³Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
4. ⁴Department of Pediatric Nephrology, University Children's Hospital, Jena, Germany
5. ⁵Department of Pediatric Nephrology, INOVA Hospital for Children, Kidney Center, Annandale, Virginia, USA
6. ⁶Department of Nephrology, Kantonsspital Lucerne, Lucerne, Switzerland
7. ⁷Department of Pediatrics, University of Michigan, Ann Arbor, USA
8. ⁸Department of Human Genetics, University of Michigan, Ann Arbor, USA

Correspondence: F Hildebrandt, Department of Pediatrics and Communicable Diseases, University of Michigan, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0646, USA. E-mail: fhilde@umich.edu

Received 23 June 2006; Revised 30 October 2006; Accepted 29 November 2006; Published online 24 January 2007.

Abstract

Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-in terstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. This disorder was described to have an age of onset between the age of 20–30 years or even later. Mutations in the Uromodulin (UMOD) gene were published in patients with familial juvenile hyperuricemic nephropathy (FJHN) and MCKD2. Clinical data and blood samples of 16 affected individuals from 11 different kindreds were collected. Mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. We found the heterozygous C744G (Cys248Trp) mutation, which was originally published by our group, in an additional four kindreds from Europe and Turkey. Age of onset ranged from 3 years to 39 years. The phenotype showed a variety of symptoms such as urinary concentration defect, vesicoureteral reflux, urinary tract infections, hyperuricemia, hypertension, proteinuria, and renal hypoplasia. Haplotype analysis showed cosegragation with the phenotype in all eight affected individuals indicating that the C744G mutation may be due to a founder effect. Moreover, we describe a novel T229G (Cys77Gly) mutation in two affecteds of one kindred. Three of the affected individuals were younger than 10 years at the onset of MCKD2/FJHN. Symptoms include recurrent urinary tract infections compatible with the published phenotype of the Umod knockout mouse model. This emphasizes that MCKD2 is not just a disease of the young adult but is also relevant for children.