title: Mutations of the Uromodulin gene in MCKD type 2 patients cluster in exon 4, which encodes three EGF-like domains.
abstract: 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 analysis 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Matthias T F
authors.initials: MT
authors.lastname: Wolf
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Mucha
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: Isabella
authors.initials: I
authors.lastname: Zalewski
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Karle
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
authors.forename: Birgit
authors.initials: B
authors.lastname: Bader
authors.forename: Conrad A
authors.initials: CA
authors.lastname: Baldamus
authors.forename: Edgar
authors.initials: E
authors.lastname: Otto
authors.forename: Ralph
authors.initials: R
authors.lastname: Witzgall
authors.forename: Arno
authors.initials: A
authors.lastname: Fuchshuber
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000737:chemistry / Q000235:genetics*; D005810:Multigene Family; D010375:Pedigree; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D017434:Protein Structure, Tertiary; D058949:Uromodulin
chemical_list: D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin; D004815:Epidermal Growth Factor