A novel pattern of mutation in uromodulin disorders: autosomal dominant medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, and autosomal dominant glomerulocystic kidney disease.
BACKGROUND
Autosomal dominant medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and autosomal dominant glomerulocystic kidney disease (GCKD) constitute a hereditary renal disease group that may lead to end-stage renal failure caused by mutations of the UMOD gene and its product, uromodulin or Tamm-Horsfall protein. Of 34 different UMOD mutations described to date, 28 were located in exon 4. Based on such mutation clustering, some investigators have proposed that the sequencing of UMOD exon 4 might become a preliminary diagnostic test for patients with this phenotype.


METHODS
We performed linkage analysis and sequencing of the entire codifying region of the UMOD gene in 4 Spanish families with MCKD/FJHN/GCKD.


RESULTS
All families were shown to present mutations in the UMOD gene. In 3 families, the detected mutations were located in exon 5. Although 1 novel mutation (Gln316Pro) was observed in 2 of these families, a previously reported mutation (Cys300Gly) was found in the other kindred. The Cys300Gly mutation was found in the family presenting with a GCKD phenotype.


CONCLUSIONS
Our data show a novel mutation pattern in UMOD , suggesting that exon 5 mutations can be more frequent in some populations. Our results support that every exon of the UMOD gene must be included in molecular testing and provide additional evidence for the existence of a fourth calcium-binding epidermal growth factor-like domain in the structure of Tamm-Horsfall protein. A second family reported to date is described, confirming that the GCKD phenotype may be caused by a UMOD mutation.
Lens
Xosé M
XM
Laboratorio de Investigación en Nefroloxía, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. xose.manuel.lens.neo@sergas.es
Banet
Julio F
JF
Outeda
Patricia
P
Barrio-Lucía
Vicente
V
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006801:Humans; D033461:Hyperuricemia / Q000453:epidemiology / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013030:Spain / Q000453:epidemiology; D013045:Species Specificity; D058949:Uromodulin
D009088:Mucoproteins; C548612:UMOD protein, human; D058949:Uromodulin