Abstract
Loss-of-function mutations in the WRN helicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide polymorphisms have been identified in WRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. Family studies of probands identified ten additional TT homozygotes. Biochemical analysis of WRN protein purified from TT lymphoblast cell lines confirmed that the R834C substitution strongly and selectively reduces WRN helicase, but not exonuclease activity. Replication track analyses showed reduced replication fork progression in some homozygous cells following DNA replication stress. Among the thirteen TT homozygotes, we identified a previously unreported and statistically significant gender bias in favor of males (p = 0.0016), but none of the clinical findings associated with Werner syndrome. Our results indicate that WRN helicase activity alone is not rate-limiting for the development of clinical WS.
Highlights
Werner syndrome (WS) is a segmental progeroid and genomic instability disorder [refs 1,2 and references therein]
We show here that this variant is present at a high frequency in the Mexican population, and took advantage of this finding to determine whether selective reduction of WRN helicase activity contributes to premature aging, genomic instability, or other phenotypes
Our findings indicate that homozygous TT individuals who have close to 90% reduction of WRN helicase activity do not present signs or symptoms diagnostic of Werner syndrome in the Mexican population
Summary
Helicase-Inactivating Variant, R834C, does not confer a Werner received: November 2016 accepted: February 2017 Published: 09 March 2017 syndrome clinical phenotype. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. We show here that this variant is present at a high frequency in the Mexican population, and took advantage of this finding to determine whether selective reduction of WRN helicase activity contributes to premature aging, genomic instability, or other phenotypes. In contrast to WS where there is a 1:1 ratio of male: female patients[17], we observe a statistically significant gender bias in favor of males among homozygous TT individuals This observation raises the possibility that WRN helicase activity may play a role in germ cell development and/or X-chromosome inactivation
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