TY - JOUR
T1 - The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect
AU - Wolf, M. T F
AU - Beck, B. B.
AU - Zaucke, F.
AU - Kunze, A.
AU - Misselwitz, J.
AU - Ruley, J.
AU - Ronda, T.
AU - Fischer, A.
AU - Eifinger, F.
AU - Licht, C.
AU - Otto, E.
AU - Hoppe, B.
AU - Hildebrandt, F.
N1 - Funding Information:
We thank all members of the MCKD families for their participation. We thank Professor R Witzgall (University of Regensburg) for providing us the UMOD antibody. The technical assistance of Steffi Schneider is gratefully acknowledged. Sources of support: Professor Hildebrandt: the Fritz-Thyssen-Stiftung (1999–2001) and DFG-Fu202/3–2, Germany. Dr Wolf: the Koeln Fortune Program Faculty of Medicine, University of Cologne (184/2004), Deutsche Nierenstiftung, and the German Research Foundation (DFG WO 1229/2–1), Germany.
PY - 2007/3/13
Y1 - 2007/3/13
N2 - 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.
AB - 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.
KW - FJHN
KW - MCKD2
KW - Tamm-Horsfall protein
KW - Uromodulin
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U2 - 10.1038/sj.ki.5002089
DO - 10.1038/sj.ki.5002089
M3 - Article
C2 - 17245395
AN - SCOPUS:33947128725
SN - 0085-2538
VL - 71
SP - 574
EP - 581
JO - Kidney international
JF - Kidney international
IS - 6
ER -