A Novel UMOD Mutation (c.187T>C) in a Korean Family with Juvenile Hyperuricemic Nephropathy
A 16-yr-old boy developed swelling and pain of the right malleolus about two weeks before hospitalization. He was evaluated at a local clinic and was treated with prednisolone under the diagnosis of hyperuricemia, gouty arthritis, and renal insufficiency. He was transferred to the department of nephrology at our hospital for further evaluation and proper management of abnormal renal function. At admission, his vital signs were stable and no symptoms related to azotemia were observed. Physical examinations, electrocardiography, and simple radiography did not reveal any abnormal findings. Blood urea nitrogen and serum creatinine levels were 36.9 and 2.12 mg/dL, respectively. Laboratory tests revealed hyperuricemia (uric acid, 10.3 mg/dL) and renal under-excretion of urate (24 hr urine uric acid, 9.6 g/day). Urine analysis showed mild hematuria (150 red blood cells/µL) and albuminuria (75 mg/dL). Other laboratory test results were within normal limits. Abdominal sonography showed normal size and echogenicity in both kidneys, with no other structural abnormality. Renal biopsy showed chronic parenchymal damage, coexisting with IgA nephropathy.\nThe proband had a family history of hyperuricemia, with his father and an elder brother having previously been diagnosed with hyperuricemia and gout. His father had received renal transplantation due to ESRD at the age of 34 in 1996. Considering the familial history, juvenile onset of hyperuricemia, gouty arthritis, and progressive renal impairment at early age, FJHN was highly suggested.\nAfter obtaining written informed consent from all subjects, peripheral blood samples were obtained. Genomic DNA was extracted from peripheral blood leukocytes by using the Wizard Genomic DNA Purification kit (Promega, Madison, WI, USA), following the manufacturer's instructions. Two exons (exons 3 and 4) of the UMOD and their flanking introns were amplified using primer sets designed by the authors (available upon request). The PCR was performed with a thermal cycler (model 9700, Applied Biosystems, Foster City, CA, USA) as follows: 32 cycles of denaturation at 94℃ for 30 sec, annealing at 60℃ for 30 sec, and extension at 72℃ for 30 sec. After treatment of the amplicon (5 µL) with 10 U shrimp alkaline phosphatase and 2 U exonuclease I (USB Corp., Cleveland, OH, USA), direct sequencing was performed with the BigDye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems) on the ABI Prism 3130xl genetic analyzer (Applied Biosystems).\nSequence analysis revealed a novel heterozygous missense variation (c.187T>C; p.Cys63Arg) in exon 3 (). PolyPhen (Polymorphism Phenotyping, ) and SIFT (Sorting Tolerant from Intolerant, ) programs predicted the p.Cys63Arg change to be "probably damaging" (PSIC score=3.410) and "affecting protein function," respectively. Both the father and an elder brother of the proband also carried the same variation. The variation identified in this family altered an evolutionary conserved residue in the UMOD.\nThe patient was treated with allopurinol (50-100 mg/day) and colchicine (0.6 mg/day) and his serum uric acid level began to decrease. Seven months later, his serum uric acid and serum creatinine levels were 8 mg/dL and 2.32 mg/dL, respectively. The elder brother was also treated with allopurinol and colchicine and both he and the proband have not developed ESRD to date and have remained clinically asymptomatic throughout this period.