Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41.
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.
Hodanová
Katerina
K
Center for Applied Genomics, Institute for Inherited Metabolic Disorders, Charles University 1st School of Medicine, Prague, Czech Republic.
Majewski
Jacek
J
Kublová
Martina
M
Vyletal
Petr
P
Kalbácová
Marie
M
Stibůrková
Blanka
B
Hůlková
Helena
H
Chagnon
Yvon C
YC
Lanouette
Christian-Marc
CM
Marinaki
Anthony
A
Fryns
Jean-Pierre
JP
Venkat-Raman
Gopalakrishnan
G
Kmoch
Stanislav
S
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
D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin