WRNMutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Abstract

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Biallelic WRN Mutations in Newly Identified Japanese Werner Syndrome Patients

“…This patient carried a heterozygous Japanese founder mutation and a compound missense variant, c.1720G>A, p.Gly574Arg. The p.Gly574Arg was previously reported in a single German patient as a compound heterozygous mutation [Tadokoro et al, 2013;Yokote et al, 2017]. Although biochemical studies had already demonstrated the abrogation of enzymatic activities in a recombinant WRN protein with p.Gly574Arg [Tadokoro et al, 2013], the identification of the second p.Gly574Arg case further strengthens the notion of the pathogenicity of this variant and the loss of enzymatic activity as the cause of the WRN mutation.…”

“…Most of the pathogenic variants of the WRN gene were null mutations, either splicing, stop codon, or small indels [Yokote et al, 2017]. Amino acid substations within the exonuclease domain found in a German patient causes protein instability [Huang et al, 2006]; thus, they were also functionally null.…”

“…Amino acid substations within the exonuclease domain found in a German patient causes protein instability [Huang et al, 2006]; thus, they were also functionally null. There have been only 2 likely pathogenic missense variants, namely p.Arg637>Trp and p.Gly574Arg [Uhrhammer et al, 2006;Tadokoro et al, 2013;Yokote et al, 2017], both of which were found in the compound heterozygotes with null mutations. Of those, only p.Gly574Arg was pathogenic [Tadokoro et al, 2013].…”

“…More than 80 different WRN pathogenic variants have been reported from all over the world [Huang et al, 2006;Yokote et al, 2017]. Due to the presence of founder mutations, Japan and the region of Sardinia in Italy are among countries with the highest frequencies of WS [Satoh et al, 1999;Masala et al, 2007;Goto et al, 2013].…”

RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting

“…Virtually all pathogenic variants of WRN are null variants, with a few exceptions of amino acid substitutions that abolish its helicase activity and those that provoke protein instability, as reviewed by George M. Martin (International Registry of Werner Syndrome, University of Washington, USA) (Yokote et al, 2017). The most common initial symptom, which is often recognized retrospectively, is the lack of a growth spurt during one’s teens.…”