WRN Mutation 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 In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations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.

Keywords: Progeroid syndrome; RECQ3; RECQL2; RecQ helicase; WRN; Werner syndrome.

Figure 1

WRN mutation update. The 35 exons of WRN gene locus and WRN protein are shown. Exon 1 and part of 35 are non-coding. The relationship between exons and functional domains is indicated by extending a shaded region from the gene region to the protein functional domains. Known functional domains are indicated by the shaded regions extending from the gene to the protein functional domains. Those domains are the exonuclease and helicase domains, RecQ helicase conserved region (RQC), helicase RNaseD C-terminal conserved region (HRDC), and the nuclear localization signal (NLS). Mutations are grouped by the types shown on the left. Large genomic rearrangements are shown on top using horizontal brackets, labeled “Dup” for duplication or “Del” for deletion. Mutations that affect splicing are indicated with inverted triangles above the WRN locus. Small genomic changes, such as insertions and deletions (Indels), are indicated below the gene locus, using a black-filled diamond shape (◆), whereas stop codons are indicated with a closed triangle (▲). Missense mutations are indicated with black-filled circles (●). Newly identified mutations are indicated for all mutation types by an asterisk (*).

Figure 2

Frequencies of WRN mutations among non-Japanese and Japanese cases. Frequent mutations of 112 non-Japanese cases in International Registry (Left) and 42 Japanese Consortium (right) are shown.

Figure 3

Countries of origin of genetically confirmed Werner syndrome patients. In black are countries (Japan and Sardinia, Italy) with known founder mutations with heterozygous frequencies of approximately 1/150. Dark gray indicates countries with possible founder mutations where more than three independent pedigrees with the same mutations have been reported. In light gray are countries with WS patients with documented WRN mutations.