Elsevier

The Lancet

Volume 362, Issue 9382, 9 August 2003, Pages 440-445
The Lancet

Mechanisms of Disease
LMNA mutations in atypical Werner's syndrome

https://doi.org/10.1016/S0140-6736(03)14069-XGet rights and content

Summary

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.

Findings

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.

Interpretation

Our findings indicate that Werner's syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.

Introduction

Werner's syndrome is an autosomal, recessively inherited, segmental progeroid syndrome, in which multiple aspects (or segments) of ageing phenotypes seem to be entailed. The disorder is caused by mutations in WRN, which is a member of the RECQ family of DNA helicases.1 We used a set of clinical criteria to prospectively classify patients enrolled in a positional cloning study that defined the locus of this gene.2 When we did not find any mutations in WRN, we tentatively designated these patients as having atypical Werner's syndrome (or non- WRN).

Several diseases that overlap partly with the phenotype of Werner's syndrome share mutations at the LMNA (lamin A/C) gene; they have therefore been referred to as laminopathies.3 These diseases include Emery-Dreifuss muscular dystrophy,4, 5 dilated cardiomyopathy type 1A,6 limb-girdle muscular dystrophy type 1B,7 familial partial lipodystrophy,7, 8, 9, 10 Charcot-Marie-Tooth disease type 2,9 mandibuloacral dysplasia,11 and a rare childhood syndrome of premature ageing, Hutchinson-Gilford syndrome.12, 13, 14 LMNA mutations causing familial partial lipodystrophy, for example, are associated with insulin resistance, type 2 diabetes, and atherosclerosis; these features are similar to those seen in people with Werner's syndrome. These observations prompted us to investigate the LMNA gene in our subset of individuals with atypical (non-WRN) Werner's syndrome.

Section snippets

Methods

Between January, 1987, and November, 2003, we enrolled all patients diagnosed with Werner's syndrome via the international registry of Werner syndrome.15 Criteria for diagnosis of Werner's syndrome are summarised in table 1. We enrolled controls from the national long-term care survey (Department of Pathology, University of Washington, Seattle, WA, USA), a population-based sampling of US residents. Written informed consent was sought at the time of enrolment from both patients and controls.

We

Results

Of 129 adult index cases referred to the University of Washington international registry of Werner syndrome, 26 (20%) did not have mutations in coding regions of WRN. Of these, four were found to be heterozygous for missense mutations in LMNA. The clinical features of these four patients are summarised in table 1, and abbreviated pedigrees are shown in figure 1.

Unlike patients with classic Werner's syndrome, who have a mean age of diagnosis of 39 years (SD 7·7),20 those diagnosed with atypical

Discussion

We have shown that a subset of patients with Werner's syndrome without mutations at the WRN locus have mutations at the LMNA locus that cause the disorder. These observations, however, do not preclude the possibility that a WRN function or functions could be altered.

Imura and colleagues24 grouped patients with Werner's syndrome according to similar clusters of clinical features. They inferred that there were at least three distinct clinical types of the disease, with type 2 Werner's syndrome

GLOSSARY

alternative splicing
A mechanism by which different forms of mature mRNAs are generated from the same gene.
amphipathic
A compound containing both hydrophobic and hydrophilic groups. An amphipathic helix contains hydrophobic aminoacids at one side and hydrophilic aminoacids at the other.
haploinsufficiency
Arises when the normal phenotype requires the protein product of both alleles, and reduction of 50% of gene function results in an abnormal phenotype.
helicases
Enzymes that unwind double-strand DNA

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