Hutchinson–Gilford progeria syndrome with scleroderma‐like skin changes due to a homozygous missense <scp>LMNA</scp> mutation

Zhang, S.; Zhang, K.; Zhao, Jingjun

doi:10.1111/jdv.12840

Cited by 6 publications

(5 citation statements)

References 8 publications

(8 reference statements)

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“…As in both the publicly available studies WS patients were not selected on the basis of a SSc-like phenotype, we can suggest that SSc-related epigenetic changes are an intrinsic characteristic of WS. Although further studies should confirm our findings, they could be particularly interesting since recent studies highlight that another progeroid disease, the Hutchinson-Gilford progeria syndrome, is associated with SSc-like skin changes [ 54 , 55 ] and that SSc-associated fibrosis is considered as an accelerated ageing phenotype [ 56 ].…”

Section: Discussionmentioning

confidence: 62%

Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

et al. 2017

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BackgroundWerner syndrome is a progeroid disorder characterized by premature age-related phenotypes. Although it is well established that autosomal recessive mutations in the WRN gene is responsible for Werner syndrome, the molecular alterations that lead to disease phenotype remain still unidentified.ResultsTo address whether epigenetic changes can be associated with Werner syndrome phenotype, we analysed genome-wide DNA methylation profile using the Infinium MethylationEPIC BeadChip in the whole blood from three patients affected by Werner syndrome compared with three age- and sex-matched healthy controls. Hypermethylated probes were enriched in glycosphingolipid biosynthesis, FoxO signalling and insulin signalling pathways, while hypomethylated probes were enriched in PI3K-Akt signalling and focal adhesion pathways. Twenty-two out of 47 of the differentially methylated genes belonging to the enriched pathways resulted differentially expressed in a publicly available dataset on Werner syndrome fibroblasts. Interestingly, differentially methylated regions identified CERS1 and CERS3, two members of the ceramide synthase family. Moreover, we found differentially methylated probes within ITGA9 and ADAM12 genes, whose methylation is altered in systemic sclerosis, and within the PRDM8 gene, whose methylation is affected in dyskeratosis congenita and Down syndrome.ConclusionsDNA methylation changes in the peripheral blood from Werner syndrome patients provide new insight in the pathogenesis of the disease, highlighting in some cases a functional correlation of gene expression and methylation status.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0389-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 62%

Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

et al. 2017

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“…Conversely, over 500 missense LMNA mutations have been recognized that mainly affected the progeny of mesenchymal stem cells [76,77]. Patients with LMNA mutations often experienced multiple phenotypes, including defects in skeletal and cardiac muscles and loss of subcutaneous adipose tissue, such as in Emery-Dreifuss muscular dystrophy (EDMD) and Dunnigan-type familial partial lipodystrophy (FPLD) [78], as well as peripheral nerve dysfunctions, or disorders resembling aging syndromes in young patients (Hutchinson-Gilford progeria syndrome (HGPS)) [79]. given its lethality in newborns [82,83].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Understanding lamin proteins and their roles in aging and cardiovascular diseases

Jiang

2018

Life Sciences

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The occurrence of cardiovascular diseases increases with age independent of other risk factors, and the percentage of senescent cells is significantly elevated in vascular cells at atherosclerotic sites. Patients with accelerated aging syndromes caused by mutant lamin A protein, a structural component in nuclear lamina, also share many similarities with normal aged people, including the propensity to develop atherosclerosis. Recent studies have revealed the accumulation of prelamin A in normal aged vascular cells, and that lamin A participated as a mechanosensitive molecule in regulating various cellular events. These findings suggest that the ectopic expression of mutant lamin A or lamin A precursor (prelamin A) not only causes defects in cell mechanics, but it also disturbs stress-induced mechanotransduction pathways involving lamin A, both of which may contribute to vascular dysregulation. This review summarizes the current understanding of how lamin proteins are involved in vascular cell during aging, with a particular focus on the effect of mechanical stresses from blood flow on nuclear lamina of endothelial cells. Related studies are clarifying the role of lamin A in the progression of atherosclerosis, which will aid in the development of potential therapies for those suffering from lamin A-associated accelerated aging syndromes.

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“…For progeroid laminopathies the time of onset of the disease, set of symptoms and severity depend on the type of mutations [14,15,16,17,18]. The vast majority of autosomal dominant type of the progeric laminopathies arise from the so-called “classical” mutation in the LMNA gene—this mutation causes HGPS [19,20].…”

Section: Phenotype and Genetic Backgroundmentioning

confidence: 99%

Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment

Piekarowicz

Machowska

Dzianisava

et al. 2019

Cells

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Hutchinson-Gilford progeria syndrome (HGPS) is one of the most severe disorders among laminopathies—a heterogeneous group of genetic diseases with a molecular background based on mutations in the LMNA gene and genes coding for interacting proteins. HGPS is characterized by the presence of aging-associated symptoms, including lack of subcutaneous fat, alopecia, swollen veins, growth retardation, age spots, joint contractures, osteoporosis, cardiovascular pathology, and death due to heart attacks and strokes in childhood. LMNA codes for two major, alternatively spliced transcripts, give rise to lamin A and lamin C proteins. Mutations in the LMNA gene alone, depending on the nature and location, may result in the expression of abnormal protein or loss of protein expression and cause at least 11 disease phenotypes, differing in severity and affected tissue. LMNA gene-related HGPS is caused by a single mutation in the LMNA gene in exon 11. The mutation c.1824C > T results in activation of the cryptic donor splice site, which leads to the synthesis of progerin protein lacking 50 amino acids. The accumulation of progerin is the reason for appearance of the phenotype. In this review, we discuss current knowledge on the molecular mechanisms underlying the development of HGPS and provide a critical analysis of current research trends in this field. We also discuss the mouse models available so far, the current status of treatment of the disease, and future prospects for the development of efficient therapies, including gene therapy for HGPS.

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Hutchinson–Gilford progeria syndrome with scleroderma‐like skin changes due to a homozygous missense LMNA mutation

Cited by 6 publications

References 8 publications

Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

Genome-wide DNA methylation analysis in blood cells from patients with Werner syndrome

Understanding lamin proteins and their roles in aging and cardiovascular diseases

Hutchinson-Gilford Progeria Syndrome—Current Status and Prospects for Gene Therapy Treatment

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