title: Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.
abstract: BACKGROUND
  Autosomal-dominant juvenile hyperuricemia, gouty arthritis, medullary cysts, and progressive renal insufficiency are features associated with familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2). MCKD1 has been mapped to chromosome 1q21. FJHN and MCKD2 have been mapped to chromosome 16p11.2. FJHN and MCKD2 are allelic, result from uromodulin (UMOD) mutations and the term uromodulin-associated kidney disease (UAKD) has been proposed for them. Linkage studies also reveal families that do not show linkage to any of the identified loci. To identify additional UAKD loci, we analyzed one of these families, with features suggestive of FJHN.
  
  
  METHODS
  Clinical, biochemical, and immunohistochemical investigations were used for phenotype characterization. Genotyping, linkage and haplotype analyses were employed to identify the candidate disease region. Bioinformatics and sequencing were used for candidate gene selection and analyses.
  
  
  RESULTS
  We identified a new candidate UAKD locus on chromosome 1q41, bounded by markers D1S3470 and D1S1644. We analyzed and found no linkage to this region in eight additional families, who did not map to the previously established loci. We noted that affected individuals showed, in addition to the characteristic urate hypoexcretion, significant reductions in urinary excretion of calcium and UMOD. Immunohistochemical analysis showed that low UMOD excretion resulted from its reduced expression, which is a different mechanism to intracellular UMOD accumulation observed in cases with UMOD mutations.
  
  
  CONCLUSIONS
  We have mapped a new candidate UAKD locus and shown that UAKD may be a consequence of various defects affecting uromodulin biology.
authors.affiliation: Center for Applied Genomics, Institute for Inherited Metabolic Disorders, Charles University 1st School of Medicine, Prague, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hodanová
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Martina
authors.initials: M
authors.lastname: Kublová
authors.forename: Petr
authors.initials: P
authors.lastname: Vyletal
authors.forename: Marie
authors.initials: M
authors.lastname: Kalbácová
authors.forename: Blanka
authors.initials: B
authors.lastname: Stibůrková
authors.forename: Helena
authors.initials: H
authors.lastname: Hůlková
authors.forename: Yvon C
authors.initials: YC
authors.lastname: Chagnon
authors.forename: Christian-Marc
authors.initials: CM
authors.lastname: Lanouette
authors.forename: Anthony
authors.initials: A
authors.lastname: Marinaki
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Gopalakrishnan
authors.initials: G
authors.lastname: Venkat-Raman
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D033461:Hyperuricemia / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009088:Mucoproteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D051436:Renal Insufficiency, Chronic / Q000235:genetics* / Q000378:metabolism; D058949:Uromodulin
chemical_list: D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin