LMNA mutations in atypical Wernerʹs syndrome

Background Wernerʹs syndrome is a progeroid syndrome caused by mutations at the WRN helicase locus. Some features of this disorder are also present in laminopathies caused by mutant LMNA encoding nuclear lamin A/C. Because of this similarity, we sequenced LMNA in individuals with atypical Wernerʹs syndrome (wild-type WRN). Methods Of 129 index patients referred to our international registry for molecular diagnosis of Wernerʹs syndrome, 26 (20%) had wildtype WRN coding regions and were categorised as having atypical Wernerʹs syndrome on the basis of molecular criteria. We sequenced all exons of LMNA in these individuals. Mutations were confirmed at the mRNA level by RT-PCR sequencing. In one patient in whom an LMNA mutation was detected and fibroblasts were available, we established nuclear morphology and subnuclear localisation. Findings In four (15%) of 26 patients with atypical Wernerʹs syndrome, we noted heterozygosity for novel missense mutations in LMNA, specifically A57P, R133L (in two people), and L140R. The mutations altered relatively conserved residues within lamin A/C. Fibroblasts from the patient with the L140R mutation had a substantially enhanced proportion of nuclei with altered morphology and mislocalised lamins. Individuals with atypical Wernerʹs syndrome with mutations in LMNA had a more severe phenotype than did those with the disorder due to mutant WRN. Interpretation Our findings indicate that Wernerʹs syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.