LMNA mutations in atypical Werner's syndrome

Abstract

Lishan Chen and colleagues1Chen L Lee L Kudlow BA et al.LMNA mutations in atypical Werner's syndrome.Lancet. 2003; 362: 440-445Summary Full Text Full Text PDF PubMed Scopus (345) Google Scholar describe heterozygous LMN mutations in patients with atypical Werner's syndrome. We believe their findings need to be further discussed in view of results presented by other research groups, indicating mutations at the same aminoacids as those mentioned by Chen and co-workers. The clinical phenotypes of the patients with atypical Werner's syndrome included in Chen and colleagues' study are not clear. In some instances, the list of clinical features seems to suggest atypical Hutchinson-Gilford progeria rather than Werner's syndrome. Perhaps the authors could provide a picture? The LMNA R133L mutation, which is caused by a 398G→T substitution—according to international nomenclature—and not a 813G→T substitution—as noted by the authors—has been previously described by Caux and colleagues; as noted by C Vigouroux and co-workers in the previous letter, the patient had none of the symptoms usually associated with Werner's syndrome. Thus, the LMNA R133L mutation seems associated with various diseases, ranging from Dunnigan's lipodystrophy to premature aging. Such overlaps of laminopathic phenotypes have been reported for other LMNA mutations2van der Kooi AJ Bonne G Eymard B et al.Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy.Neurology. 2002; 59: 620-623Crossref PubMed Scopus (118) Google Scholar—for example, R28W, R60G, R62G, and R527P lead to various combinations of muscular dystrophies and lipodystrophic features. The specific aminoacid substitution of arginine at position 527 of lamin A/C is of particular interest, since the substitutions reported—R527P, R527H, and R527C—result in Emery-Dreifuss muscular dystrophy (EDMD), mandibulo-acral dysplasia, and Hutchinson-Gilford progeria syndrome (HGPS), respectively.3Cao H Hegele R LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090).J Hum Genet. 2003; 48: 271-274Crossref PubMed Scopus (188) Google Scholar Similarly, two aminoacid substitutions are reported for leucine at position 140; R140P in a patient with EDMD and no symptoms of premature ageing,4Boriani G Gallina M Merlini L et al.Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study.Stroke. 2003; 34: 501-508Crossref Scopus (144) Google Scholar and R140L in a patient with atypical Werner's syndrome.1Chen L Lee L Kudlow BA et al.LMNA mutations in atypical Werner's syndrome.Lancet. 2003; 362: 440-445Summary Full Text Full Text PDF PubMed Scopus (345) Google Scholar Such a clinical heterogeneity in laminopathies might be caused by the loss of tissue-specific protein interactions when LMNA is mutated, and its underlying mechanisms should be further explored. The most common LMNA mutation that causes progeria is G608G not G608S, which has been reported in only one patient.3Cao H Hegele R LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090).J Hum Genet. 2003; 48: 271-274Crossref PubMed Scopus (188) Google Scholar, 5Eriksson M Brown WT Gordon LB et al.Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Nature. 2003; 25: 25Google Scholar With respect to nuclear morphology, results of previous analyses, such as that reported by Caux and co-workers, of fibroblasts from patients carrying LMNA mutations (R133L, R482W/Q, R527H) indicate that 10–15% of cells have dimorphic nuclei, exhibiting herniation of the nuclear envelope or honeycomb lamin A/C localisation. The proportion of fibroblasts with irregularly shaped nuclei increases to 48% for HGPS G608G mutation,5Eriksson M Brown WT Gordon LB et al.Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome.Nature. 2003; 25: 25Google Scholar and to 60% for atypical Werner's L140R mutation.1Chen L Lee L Kudlow BA et al.LMNA mutations in atypical Werner's syndrome.Lancet. 2003; 362: 440-445Summary Full Text Full Text PDF PubMed Scopus (345) Google Scholar However, in this last instance, the proportion might be overestimated, since the authors describe as mis-shapen a nucleus that has a quite normal shape (figure 4L in article). These ratios of abnormal nuclei in cells from progeria patients could underline the severity of the clinical phenotype, but systematic analyses need to be undertaken before any firm conclusions can be drawn. Why mutations in LMNA result in such a wide range of apparently distinct phenotypes is unknown. However, the identification of overlapping laminassociated disorders indicates that they represent a functional continuum of related disorders rather than separate diseases. LMNA mutations in atypical Werner's syndromeAuthors' reply Full-Text PDF