Novel
            <i>LMNA</i>
            Mutation in Atypical Werner Syndrome Presenting With Ischemic Disease

Renard, Dimitri; Fourcade, G.; Milhaud, D.; Bessis, Didier; Esteves-Vieira, Vera; Boyer, Anthony; Roll, Patrice; Bourgeois, P.; Levy, Nicolas; Sandre-Giovannoli, Annachiara De

doi:10.1161/strokeaha.108.531780

Cited by 30 publications

(33 citation statements)

References 6 publications

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“…Both HGS and WS have unique phenotypes with several overlapping clinical features. 2,7,[10][11][12][13] The analysis of our patient's LMNA gene revealed a heterozygous point mutation in exon 5, c.898G>A (p.D300N). 2 These patients have been diagnosed with APS or AWS.…”

Section: Discussionmentioning

confidence: 77%

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

Motegi

Yokoyama

Uchiyama

et al. 2014

The Journal of Dermatology

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Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

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Section: Discussionmentioning

confidence: 77%

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

Motegi

Yokoyama

Uchiyama

et al. 2014

The Journal of Dermatology

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“…This condition is referred to as atypical WS [61]. Patients with atypical WS display some of the common WS clinical features, including bird-like facies, osteoporosis, diabetes mellitus, and artherosclerosis [61–64]. Initial analysis of the genetic causes of atypical WS, revealed a set of heterozygous missense mutations within conserved residues of the LMNA gene [61, 63].…”

Section: Molecular Genetics Of Werner Syndrome (Ws)mentioning

confidence: 99%

“…Initial analysis of the genetic causes of atypical WS, revealed a set of heterozygous missense mutations within conserved residues of the LMNA gene [61, 63]. Recent studies of patients with atypical WS detect two novel mutations in LMNA : a previously unidentified missense mutation [64] and a deletion mutation [62]. While it is clear that LMNA mutations are linked with atypical WS, the mechanisms for the biological manifestation of the LMNA gene mutations has yet to be elucidated.…”

Section: Molecular Genetics Of Werner Syndrome (Ws)mentioning

confidence: 99%

Roles of Werner syndrome protein in protection of genome integrity

2010

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OverviewWerner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans (see additional reviews in this issue), as well as Sgs1 in Saccharomyces cerevisiae, Rqh1 in Schizosaccharomyces pombe, and homologs in Caenorhabditis elegans, Xenopus laevis, and Drosophila melanogaster [1]. Defects in three of the RecQ helicases, RecQ4, BLM, and WRN, cause human pathologies linked with cancer predisposition and premature aging [1][2][3][4][5]. Mutations in the WRN gene are the causative factor of Werner syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance [1][2][3][4][5][6]. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post-translational modifications, as well as several important protein-protein interactions [1,2,7]. Many of these functions of WRN in genome maintenance, as well as the clinical characteristics of WS, have been recently reviewed [8][9][10][11][12]. In this work, we will summarize some of the early studies on the cellular roles of WRN and highlight the recent findings that shed some light on the link between the protein and its cellular functions with the disease pathology. Molecular Genetics of Werner Syndrome (WS)WS is a rare autosomal recessive progeroid disorder characterized by the development of cataracts, changing of skin conditions, bird-like facies, atypical short stature, and premature graying or thinning of the hair [9]. Patients also often develop hypogonadism, osteoporosis, diabetes mellitus, artherosclerosis [13], and cancers, particularly sarcomas [14]. Onset of symptoms usually occurs in the third decade of life, and health subsequently declines with median age at death between 47-54 years [13]. Because WS presents with early-onset of conditions commonly seen in the aged, it is a good model system for the study of mechanisms of normal aging [15,16]. WRN BiochemistryThe causative factor of the majority of WS is mutation in the WRN gene, which codes for a member of the highly conserved RecQ family of helicases. While several different mutations within the gene are seen in WS, most result in production of truncated WRN protein [13]. 1Address correspondence to: Dr. Vilhelm A. Bohr, NIH Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224; BohrV@grc.nia.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the...

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“…Atypical Werner’s syndrome is a premature aging syndrome that presents at a later age than HGPS (e.g., second or third decade of life), but shares similarities with HGPS (37,57,253). Atypical Werner’s syndrome is caused by mutations in LMNA , often occurring in the first two coiled-coil domains of the lamin A protein.…”

Section: Nuclear Envelopathiesmentioning

confidence: 99%

Diseases of the Nucleoskeleton

Holaska

2016

Comprehensive Physiology

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The nucleus is separated from the cytosol by the nuclear envelope, which is a double lipid bilayer composed of the outer nuclear membrane and the inner nuclear membrane. The intermediate filament proteins lamin A, lamin B, and lamin C form a network underlying the inner nuclear membrane. This proteinaceous network provides the nucleus with its strength, rigidity, and elasticity. Positioned within the inner nuclear membrane are more than 150 inner nuclear membrane proteins, many of which interact directly with lamins and require lamins for their inner nuclear membrane localization. Inner nuclear membrane proteins and the nuclear lamins define the nuclear lamina. These inner nuclear membrane proteins have tissue-specific expression and diverse functions including regulating cytoskeletal organization, nuclear architecture, cell cycle dynamics, and genomic organization. Loss or mutations in lamins and inner nuclear membrane proteins cause a wide spectrum of diseases. Here, I will review the functions of the well-studied nuclear lamina proteins and the diseases associated with loss or mutations in these proteins. © 2016 American Physiological Society.

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Novel LMNA Mutation in Atypical Werner Syndrome Presenting With Ischemic Disease

Cited by 30 publications

References 6 publications

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

First Japanese case of atypical progeroid syndrome/atypical Werner syndrome with heterozygous LMNA mutation

Roles of Werner syndrome protein in protection of genome integrity

Diseases of the Nucleoskeleton

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