TY - JOUR
T1 - Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains
AU - Wolf, Matthias T F
AU - Mucha, Bettina E.
AU - Attanasio, Massimo
AU - Zalewski, Isabella
AU - Karle, Stephanie M.
AU - Neumann, Hartmut P H
AU - Rahman, Nazneen
AU - Bader, Birgit
AU - Baldamus, Conrad A.
AU - Otto, Edgar
AU - Witzgall, Ralph
AU - Fuchshuber, Arno
AU - Hildebrandt, Friedhelm
N1 - Funding Information:
We thank all members of the MCKD families for their participation, R.H. Lyons for excellent large-scale sequencing, and N. Hateboer for contribution of patient material. The outstanding technical assistance of Anita Imm is gratefully acknowledged. Dr. Fuchshuber was supported by a grant from the German Research Foundation (DFG Fu 202/2-1) and the Fritz-Thyssen-Stiftung (1999-2061).
PY - 2003/11
Y1 - 2003/11
N2 - Background. Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene. UMOD encodes the Tamm-Horsfall protein. By sequence analysis, one group formerly excluded UMOD as the disease-causing gene. In contrast, recently, another group described mutations in the UMOD gene as responsible for MCKD2 and familial juvenile hyperuricemic nephropathy (FJHN). Methods. Haplotype analaysis for linkage to MCKD2 was performed in 25 MCKD families. In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. Results. In 19 families, haplotype analysis was compatible with linkage to the MCKD2 locus. All these kindreds were examined for mutations in the UMOD gene. In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals. Mutations were found only in exon 4. Conclusion. We confirm the UMOD gene as the disease-causing gene for MCKD2. All three novel mutations were found in the fourth exon of UMOD, in which all mutations except one (this is located in the neighboring exon 5) published so far are located. These data point to a specific role of exon 4 encoded sequence of UMOD in the generation of the MCKD2 renal phenotype.
AB - Background. Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. The chromosomal locus for MCKD2 was localized on chromosome 16p12. Within this chromosomal region, Uromodulin (UMOD) was located as a candidate gene. UMOD encodes the Tamm-Horsfall protein. By sequence analysis, one group formerly excluded UMOD as the disease-causing gene. In contrast, recently, another group described mutations in the UMOD gene as responsible for MCKD2 and familial juvenile hyperuricemic nephropathy (FJHN). Methods. Haplotype analaysis for linkage to MCKD2 was performed in 25 MCKD families. In the kindreds showing linkage to the MCKD2 locus on chromosome 16p12, mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. Results. In 19 families, haplotype analysis was compatible with linkage to the MCKD2 locus. All these kindreds were examined for mutations in the UMOD gene. In three different families, three novel heterozygous mutations in the UMOD gene were found and segregated with the phenotype in affected individuals. Mutations were found only in exon 4. Conclusion. We confirm the UMOD gene as the disease-causing gene for MCKD2. All three novel mutations were found in the fourth exon of UMOD, in which all mutations except one (this is located in the neighboring exon 5) published so far are located. These data point to a specific role of exon 4 encoded sequence of UMOD in the generation of the MCKD2 renal phenotype.
KW - MCKD2
KW - Tamm-Horsfall protein
KW - Uromodulin
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U2 - 10.1046/j.1523-1755.2003.00269.x
DO - 10.1046/j.1523-1755.2003.00269.x
M3 - Article
C2 - 14531790
AN - SCOPUS:10744224657
SN - 0085-2538
VL - 64
SP - 1580
EP - 1587
JO - Kidney international
JF - Kidney international
IS - 5
ER -