The Uromodulin C744G mutation causes MCKD2 and FJHN in children and adults and may be due to a possible founder effect

Kidney Int. 2007 Mar;71(6):574-81. doi: 10.1038/sj.ki.5002089. Epub 2007 Jan 24.

Abstract

Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulo-in terstitial nephropathy that causes renal salt wasting, hyperuricemia, gout, and end-stage renal failure in the fifth decade of life. This disorder was described to have an age of onset between the age of 20-30 years or even later. Mutations in the Uromodulin (UMOD) gene were published in patients with familial juvenile hyperuricemic nephropathy (FJHN) and MCKD2. Clinical data and blood samples of 16 affected individuals from 11 different kindreds were collected. Mutational analysis of the UMOD gene was performed by exon polymerase chain reaction (PCR) and direct sequencing. We found the heterozygous C744G (Cys248Trp) mutation, which was originally published by our group, in an additional four kindreds from Europe and Turkey. Age of onset ranged from 3 years to 39 years. The phenotype showed a variety of symptoms such as urinary concentration defect, vesicoureteral reflux, urinary tract infections, hyperuricemia, hypertension, proteinuria, and renal hypoplasia. Haplotype analysis showed cosegragation with the phenotype in all eight affected individuals indicating that the C744G mutation may be due to a founder effect. Moreover, we describe a novel T229G (Cys77Gly) mutation in two affecteds of one kindred. Three of the affected individuals were younger than 10 years at the onset of MCKD2/FJHN. Symptoms include recurrent urinary tract infections compatible with the published phenotype of the Umod knockout mouse model. This emphasizes that MCKD2 is not just a disease of the young adult but is also relevant for children.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Child
  • Child, Preschool
  • Cystine
  • DNA Mutational Analysis
  • Europe
  • Exons / genetics
  • Female
  • Glycine
  • Haplotypes / genetics
  • Humans
  • Hyperuricemia / genetics*
  • Hyperuricemia / urine
  • Kidney Diseases / genetics*
  • Kidney Diseases / urine
  • Male
  • Middle Aged
  • Mucoproteins / genetics*
  • Mucoproteins / urine
  • Pedigree
  • Phenotype
  • Point Mutation / genetics*
  • Polycystic Kidney, Autosomal Dominant / genetics*
  • Polycystic Kidney, Autosomal Dominant / urine
  • Turkey
  • Uromodulin

Substances

  • Mucoproteins
  • UMOD protein, human
  • Umod protein, mouse
  • Uromodulin
  • Cystine
  • Glycine