Mechanisms of DiseaseLMNA mutations in atypical Werner's syndrome
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
References (32)
- et al.
Homozygosity mapping of the Werner syndrome locus (WRN)
Genomics
(1994) - et al.
Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C
Am J Hum Genet
(2000) - et al.
Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene
Am J Med
(2002) - et al.
Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C
AmJHumGenet
(2002) - et al.
Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C
J Biol Chem
(1993) - et al.
Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse
Am J Hum Genet
(2002) The nuclear envelope, muscular dystrophy and gene expression
Trends Cell Biol
(2000)- et al.
A role for both RB and p53 in the regulation of human cellular senescence
Exp Cell Res
(1991) - et al.
Roles of the Werner syndrome protein in pathways required for maintenance of genome stability
Exp Gerontol
(2002) - et al.
Positional cloning of the Werner's syndrome gene
Science
(1996)
Life at the edge: the nuclear envelope and human disease
Nat Rev Mol Cell Biol
Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy
Nat Genet
Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy
Am J Med Genet
Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease
N Engl J Med
Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B)
Hum Mol Genet
Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy
HumMolGenet
Cited by (362)
Lipodystrophy as a target to delay premature aging
2024, Trends in Endocrinology and MetabolismGeneralized lipoatrophy syndromes
2021, Presse MedicaleCell stretchers and the LINC complex in mechanotransduction
2021, Archives of Biochemistry and BiophysicsDo eye movements “age” earlier in progeria?
2020, Clinical NeurophysiologySerum levels of adiponectin differentiate generalized lipodystrophies from anorexia nervosa
2024, Journal of Endocrinological Investigation