WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations

Abstract

Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

Fig. 1

WRN mutations in WS patients. A diagram of the full-length wild-type WRN protein is shown, with its N-terminus on the left (N) and C-terminus on the right (C). Known functional domains are marked with darker shades; the exonuclease domain, the helicase domain, the RecQ helicase conserved region (RQC), the helicase RNaseD C-terminal conserved region (HDRC), and the nuclear localization signal (NLS). Mutations are grouped according to canonical classes and further identified by their amino acid changes using the reference sequence, NP_000544.2, and the nomenclature guidelines of the Human Genome Variation Society (http://www.hgvs.org/mutnomen/). Splicing mutations are indicated by the affected exons. Splicing mutations that result in identical exon skipping are combined and indicated by the number of unique mutations as in (2). Deep intron mutations that create new exons are indicated as “Ins” along with the flanking exons. Splice mutations that create a new splice site (“nss”) are indicated as such. Genomic rearrangements, either deletion (Del) or triplication (Trip), are shown at corresponding protein locations, with regions extending beyond this figure in dotted lines. Newly identified mutations and those requiring further study are also underlined. Asterisk indicates uncertainty in the interpretation of array CGH results (see text)

Fig. 2

Array CGH analyses of the WS cases involving WRN locus. Panels show result of the quantitative SNP-analysis for patients, Registry# WU1010 and CP97510. The X-axis indicates the physical position of the chromosome's 8p12 region with the telomeric region on the left and the centromeric on the right. The Y-axis of a–d indicates the copy number calculated by log₂ (test/control) ratios of the probes. a and d A scattered plot (a) and copy number plot (c) of CP97510 show an amplification (CN-State 4) with a size of approximately 60 kb in the N-terminal part of WRN. b and d A scattered plot (b) and copy number plot (d) of WU1010 show a large heterozygous deletion (CN-State 1) encompassing the C-terminal part of WRN and the first exon of NRG1 with a size of about 550 kb. e The region of copy number gain in CP97510 is indicated by a blue rectangle. The region of copy number loss in WU1010 is indicated by a red rectangle. f The chromosome band (8p12), nucleotide coordinates and the annotated loci in this region are shown with stripes that are scaled to the exact size of the deletion/gain regions on the chromosome