Elevation of Serum Hyaluronan Level in Werner’s Syndrome

Abstract

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.

KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization

“…Werner syndrome is an adult-onset progeroid disease caused by mutations in the WRN gene encoding a protein with helicase and exonuclease activities (34). Interestingly, Werner patients show hyperhyaluronic aciduria together with elevated serum HA concentration (35) and scleroderma-like skin with an aged appearance, characterized by reduced amounts of HA (36). Skin fibroblasts isolated from a patient with Werner syndrome overexpress KIAA1199 (21) and generate small molecular weight HA (37).…”

WRN promoter methylation possibly connects mucinous differentiation, microsatellite instability and CpG island methylator phenotype in colorectal cancer

“…Abnormal glycosaminoglycan metabolism is present in Werner syndrome cells, [28][29][30][31] and Werner syndrome patients show elevated levels of hyaluronic acid in serum and urine. [24][25][26][27] Thus, it is possible that abnormal glycosaminoglycan metabolism may cause mucin overproduction in colorectal cancer with WRN methylation and functional loss. This hypothesis can, at least in part, explain the well-known association between mucinous differentiation and MSI/CIMP in colorectal cancer, [20][21][22][23] as we have shown the positive correlations between WRN methylation and MSI/CIMP, and between WRN methylation and mucinous differentiation.…”

“…[24][25][26][27] WRN-deficient cells exhibit abnormal metabolism of glycosaminoglycan, [28][29][30][31] and in particular, excretion of glycosaminoglycan is increased from WRN-deficient cells. 32 Thus, we hypothesized that WRN promoter methylation and gene silencing might, at least in part, explain excessive mucin secretion in a subset of colorectal cancers with CIMP and/or MSI.…”

Werner syndrome: A changing pattern of clinical manifestations in Japan (1917-2008)

“…WS has been formerly inadvertently classified as a new group of hereditary mucopolysaccharidosis (44)(45)(46). Hyaluronan elevation either from urine and serum has been believed as a biomarker of normal aging and progeroid syndromes such as WS and progeria (46)(47)(48)(49) and the International Registry of Werner syndrome included hyaluronuria for diagnosing WS (http://www. pathology.…”