Elevation of Serum Hyaluronan Level in Werner’s Syndrome

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Background: There is a well-established association between Werner’s syndrome (WS) and hyperhyaluronic aciduria; however, to date hyaluronan (HA) in the serum has not been statistically linked with WS. Recently, the gene that causes WS has been defined as a DNA helicase on chromosome 8, and 19 different mutations in WS patients have been identified. It is not known whether the mutation type of the Werner helicase gene affects the levels of serum and urine HA in WS patients. Objective: To evaluate the association of serum HA with WS, and the relationship of the serum and urine HA levels to the mutation type. Methods: HA both in the serum and the urine was measured in 40 patients with WS and 114 normal controls. The serum and urine HA were quantified by sandwich binding protein assay and competitive ELISA-like method, respectively. The muation on WS helicase gene was analyzed by mutant-allele-specific amplification and oligomer ligation assay. Results: WS patients showed significantly higher levels of HA in the serum (mean ± SD: 115.7 ± 119.8 ng/ml, p < 0.001) and urine (1,040.8 ± 777.3 ng/mg creatinine, Cre, p < 0.001) than age-matched controls (serum HA: 15.8 ± 14.2 ng/ml, urine HA: 379.7 ± 124.2 ng/mg Cre). The serum and urine HA levels of WS patients are almost equal to those of normal controls over 80 years (serum HA: 118.5 ± 108.4 ng/ml, urine HA: 914.5 ± 712.1 ng/mg Cre). There was a significant correlation between serum and urine HA levels in WS patients (r = 0.42, p = 0.007). Analysis of the mutation on the helicase gene in 22 WS patients showed that among 44 chromosomes, 3 (6.8%) chromosomes had type 1 mutation, 22 (50.0%) had type 4 mutation, 14 (31.8%) had type 6 mutation, and the rest had other mutations. The serum and urine levels of HA did not show any significant association with the mutation type. Conclusion: The hyperhyaluronic aciduria in WS reflects the high level of serum HA. The serum and urine HA levels are useful biochemical markers for WS irrespective of the muation type of the Werner helicase gene.