title: Familial juvenile hyperuricemic nephropathy: detection of mutations in the uromodulin gene in five Japanese families.
abstract: BACKGROUND
  Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disease characterized by hyperuricemia of underexcretion type, gout, and chronic renal failure. We previously reported linkage on chromosome 16p12 in a large Japanese family designated as family 1 in the present study. Recent reports on the discovery of mutations of the uromodulin (UMOD) gene in families with FJHN encouraged us to screen UMOD mutations in Japanese families with FJHN, including family 1.
  
  
  METHODS
  Six unrelated Japanese families with FJHN were examined for mutations of the UMOD gene by direct sequencing. To confirm the results of the mutation screening, parametric linkage analyses were performed using markers in 16p12 region and around other candidate genes of FJHN.
  
  
  RESULTS
  Five separate heterozygous mutations (Cys52Trp, Cys135Ser, Cys195Phe, Trp202Ser, and Pro236Leu) were found in five families, including family 1. All mutations were co-segregated with the disease phenotype in all families, except for family 1, in which an individual in the youngest generation was found as a phenocopy by the genetic testing. Revised multipoint linkage analysis showed that the UMOD gene was located in the interval showing logarithm of odds (LOD) score above 6.0. One family carrying no mutation in the UMOD gene showed no linkage to the medullary cystic kidney disease type 1 (MCKD1) locus, the genes of hepatocyte nuclear factor-1beta (HNF-1beta), or urate transporters URAT1 and hUAT.
  
  
  CONCLUSIONS
  Our results gave an evidence for the mutation of the UMOD gene in the majority of Japanese families with FJHN. Genetic heterogeneity of FJHN was also confirmed. Genetic testing is necessary for definite diagnosis in some cases especially in the young generation.
authors.affiliation: Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima, Japan. kudo@genome.tokushima-u.ac.jp
authors.forename: Eiji
authors.initials: E
authors.lastname: Kudo
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Osamu
authors.initials: O
authors.lastname: Tezuka
authors.forename: Atsuo
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Yamanaka
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yabe
authors.forename: Dai
authors.initials: D
authors.lastname: Osabe
authors.forename: Syuichi
authors.initials: S
authors.lastname: Shinohara
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nomura
authors.forename: Masaya
authors.initials: M
authors.lastname: Segawa
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Maki
authors.initials: M
authors.lastname: Moritani
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kunika
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004247:DNA / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics*; D007564:Japan; D008297:Male; D009088:Mucoproteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D058949:Uromodulin
chemical_list: D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin; D004247:DNA