LMNA mutations in atypical Werner's syndrome.
BACKGROUND
Werner's 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 Werner's syndrome (wild-type WRN).


METHODS
Of 129 index patients referred to our international registry for molecular diagnosis of Werner's syndrome, 26 (20%) had wildtype WRN coding regions and were categorised as having atypical Werner's 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.


RESULTS
In four (15%) of 26 patients with atypical Werner's 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 Werner's syndrome with mutations in LMNA had a more severe phenotype than did those with the disorder due to mutant WRN.


CONCLUSIONS
Our findings indicate that Werner's syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.
Chen
Lishan
L
Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
Lee
Lin
L
Kudlow
Brian A
BA
Dos Santos
Heloisa G
HG
Sletvold
Olav
O
Shafeghati
Yousef
Y
Botha
Eleanor G
EG
Garg
Abhimanyu
A
Hanson
Nancy B
NB
Martin
George M
GM
Mian
I Saira
IS
Kennedy
Brian K
BK
Oshima
Junko
J
D000293:Adolescent; D002478:Cells, Cultured; D002648:Child; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005090:Exodeoxyribonucleases; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D053484:RecQ Helicases; D012042:Registries; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014898:Werner Syndrome / Q000145:classification / Q000175:diagnosis / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D034904:Lamin Type A; D009687:Nuclear Proteins; D012333:RNA, Messenger; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase