scholarly journals Generation of a Hutchinson–Gilford progeria syndrome monkey model by base editing

2020 ◽  
Vol 11 (11) ◽  
pp. 809-824 ◽  
Author(s):  
Fang Wang ◽  
Weiqi Zhang ◽  
Qiaoyan Yang ◽  
Yu Kang ◽  
Yanling Fan ◽  
...  
Keyword(s):  
De Novo ◽  
Single Point ◽  
Point Mutations ◽  
Premature Aging ◽  
Single Amino Acid ◽  
Patient Specific ◽  
Disease Models ◽  
Monkey Model ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Abstract Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.

Hutchinson–Gilford Progeria Syndrome (Hgps) And Application Of Gene Therapy Based Crispr/Cas Technology As A Promising Innovative Treatment Approach

2021 ◽  
Vol 15 ◽  
Author(s):  
Mekha Rajeev ◽  
Chameli Ratan ◽  
Karthik Krishnan ◽  
Meenu Vijayan
Keyword(s):  
De Novo ◽  
Treatment Approach ◽  
Genetic Disorder ◽  
Symptomatic Relief ◽  
Dominant Negative ◽  
Premature Aging ◽  
Lamin A ◽  
Promising Therapeutic Approach ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Background: Hutchinson–Gilford progeria syndrome (HGPS) also known as progeria of childhood or progeria is a rare, rapid, autosomal dominant genetic disorder characterized by premature aging which occurs shortly after birth. HGPS occurs as a result of de novo point mutation in the gene recognized as LMNA gene that encodes two proteins Lamin A protein and Lamin C protein which are the structural components of the nuclear envelope. Mutations in the gene trigger abnormal splicing and induce internal deletion of 50 amino acids leading to the development of a truncated form of Lamin A protein known as Progerin. Progerin generation can be considered as the crucial step in HGPS since the protein is highly toxic to human cells, permanently farnesylated, and exhibits variation in several biochemical and structural properties within the individual. HGPS also produces complications such as skin alterations, growth failure, atherosclerosis, hair and fat loss, and bone and joint diseases. We have also revised all relevant patents relating to Hutchinson-gilford progeria syndrome and its therapy in the current article. Method: The goal of the present review article is to provide information about Hutchinson–Gilford progeria syndrome (HGPS) and the use of CRISPR/Cas technology as a promising treatment approach in the treatment of the disease. The review also discusses about different pharmacological and non-pharmacological methods of treatment currently used for HGPS. Results : The main limitation associated with progeria is the lack of a definitive cure. The existing treatment modality provides only symptomatic relief. Therefore, it is high time to develop a therapeutic method that hastens premature aging in such patients. Conclusion: CRISPR/Cas technology is a novel gene-editing tool that allows genome editing at specific loci, and is found to be a promising therapeutic approach for the treatment of genetic disorders such as HGPS where dominant-negative mutations take place.

Emerging candidate treatment strategies for Hutchinson-Gilford progeria syndrome

2017 ◽  
Vol 45 (6) ◽  
pp. 1279-1293 ◽  
Author(s):  
Charlotte Strandgren ◽  
Gwladys Revêchon ◽  
Agustín Sola Carvajal ◽  
Maria Eriksson
Keyword(s):  
De Novo ◽  
Disease Incidence ◽  
Treatment Strategies ◽  
Premature Aging ◽  
Lamin A ◽  
Lmna Gene ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS, progeria) is an extremely rare premature aging disorder affecting children, with a disease incidence of ∼1 in 18 million individuals. HGPS is usually caused by a de novo point mutation in exon 11 of the LMNA gene (c.1824C>T, p.G608G), resulting in the increased usage of a cryptic splice site and production of a truncated unprocessed lamin A protein named progerin. Since the genetic cause for HGPS was published in 2003, numerous potential treatment options have rapidly emerged. Strategies to interfere with the post-translational processing of lamin A, to enhance progerin clearance, or directly target the HGPS mutation to reduce the progerin-producing alternative splicing of the LMNA gene have been developed. Here, we give an up-to-date resume of the contributions made by our and other research groups to the growing list of different candidate treatment strategies that have been tested, both in vitro, in vivo in mouse models for HGPS and in clinical trials in HGPS patients.

scholarly journals RISK FACTORS, PREVALENCE AND DIAGNOSIS OF HUTCHISON GILFORD SYNDROME WITH SPECIAL REFERENCE TO CASE REPORTS

2017 ◽  
Vol 9 (5) ◽  
pp. 1
Author(s):  
Bhawana Sharma ◽  
Priyanka Sharma ◽  
S. C. Joshi
Keyword(s):  
Splice Site ◽  
De Novo ◽  
Case Reports ◽  
Genetic Disorder ◽  
Subcutaneous Fat ◽  
Point Mutations ◽  
Lamin A ◽  
Laboratory Findings ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Progeria also known Hutchinson–Gilford progeria syndrome (HGPS), is an extremely rare genetic disorder. The prevalence of HGPS is 1 in 4-8 million newborns. Progeria causes premature, rapid aging shortly after birth present within the first year of life. Recently, de novo point mutations in the Lmna gene at position 1824 of the coding sequence have been found in persons with HGPS. Lmna encodes lamin A and C, the A-type lamins, which are an important structural component of the nuclear envelope and play a role in protein processing. The most common HGPS mutation is located at codon 608 (G608G). This mutation responsible for creating a cryptic splice site within exon 11, which deletes a proteolytic cleavage site within the expressed mutant lamin A. In Progeria, gene mutation results in the deletion of a Zmpste24/FACE1 splice site in prelamin A, preventing end terminal cleavage. The result of this point mutation can be observed by the main clinical and radiological features include alopecia, thin skin hypoplasia of nails, loss of subcutaneous fat, and osteolysis. The common symptoms of HGPS is a loss of eyebrows and eyelashes which can observed in early childhood and due to receding hairline and blading can also observed. Generally, this patient has facial character include microganthia (small jaw), craniofacial disproportion, prominent eyes, scalp veins and alopecia (loss of hair), restricted joint mobility and severe premature atherosclerosis. Laboratory findings are unremarkable, with the exception of an increased urinary excretion of hyaluronic acid. There is presently no effective therapy is available for Hutchinson-Gilford progeria syndrome (HGPS) but, it is essential to monitor carefully cardiovascular and cerebrovascular disease So, Treatment usually includes low dose aspirin which helps prevent the atherothrombotic events, stroke and heart attacks by hindering platelet aggregation

scholarly journals Baricitinib, a JAK-STAT Inhibitor, Reduces the Cellular Toxicity of the Farnesyltransferase Inhibitor Lonafarnib in Progeria Cells

2021 ◽  
Vol 22 (14) ◽  
pp. 7474
Author(s):  
Rouven Arnold ◽  
Elena Vehns ◽  
Hannah Randl ◽  
Karima Djabali
Keyword(s):  
De Novo ◽  
Early Death ◽  
Premature Aging ◽  
Farnesyltransferase Inhibitor ◽  
Cellular Toxicity ◽  
Signaling Axis ◽  
Cellular Stresses ◽  
Exon 11 ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is an ultra-rare multisystem premature aging disorder that leads to early death (mean age of 14.7 years) due to myocardial infarction or stroke. Most cases have a de novo point mutation at position G608G within exon 11 of the LMNA gene. This mutation leads to the production of a permanently farnesylated truncated prelamin A protein called “progerin” that is toxic to the cells. Recently, farnesyltransferase inhibitor (FTI) lonafarnib has been approved by the FDA for the treatment of patients with HGPS. While lonafarnib treatment irrefutably ameliorates HGPS disease, it is however not a cure. FTI has been shown to cause several cellular side effects, including genomic instability as well as binucleated and donut-shaped nuclei. We report that, in addition to these cellular stresses, FTI caused an increased frequency of cytosolic DNA fragment formation. These extranuclear DNA fragments colocalized with cGAs and activated the cGAS-STING-STAT1 signaling axis, upregulating the expression of proinflammatory cytokines in FTI-treated human HGPS fibroblasts. Treatment with lonafarnib and baricitinib, a JAK-STAT inhibitor, not only prevented the activation of the cGAS STING-STAT1 pathway, but also improved the overall HGPS cellular homeostasis. These ameliorations included progerin levels, nuclear shape, proteostasis, cellular ATP, proliferation, and the reduction of cellular inflammation and senescence. Thus, we suggest that combining lonafarnib with baricitinib might provide an opportunity to reduce FTI cellular toxicity and ameliorate HGPS symptoms further than lonafarnib alone.

scholarly journals Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome

Nature ◽  
2003 ◽  
Vol 423 (6937) ◽  
pp. 293-298 ◽  
Author(s):  
Maria Eriksson ◽  
W. Ted Brown ◽  
Leslie B. Gordon ◽  
Michael W. Glynn ◽  
Joel Singer ◽  
...  
Keyword(s):  
De Novo ◽  
Point Mutations ◽  
Lamin A ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Disrupting the LINC complex in smooth muscle cells reduces aortic disease in a mouse model of Hutchinson-Gilford progeria syndrome

2018 ◽  
Vol 10 (460) ◽  
pp. eaat7163 ◽  
Author(s):  
Paul H. Kim ◽  
Jennings Luu ◽  
Patrick Heizer ◽  
Yiping Tu ◽  
Thomas A. Weston ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
De Novo ◽  
Muscle Cells ◽  
Aortic Disease ◽  
Premature Aging ◽  
Linc Complex ◽  
De Novo Mutations ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome is a disorder of premature aging in children caused by de novo mutations in LMNA that lead to the synthesis of an internally truncated form of prelamin A (commonly called progerin). The production of progerin causes multiple disease phenotypes, including an unusual vascular phenotype characterized by the loss of smooth muscle cells in the arterial media and fibrosis of the adventitia. We show that progerin expression, combined with mechanical stress, promotes smooth muscle cell death. Disrupting the linker of the nucleoskeleton and cytoskeleton (LINC) complex in smooth muscle cells ameliorates the toxic effects of progerin on smooth muscle cells and limits the accompanying adventitial fibrosis.

scholarly journals Comparison of Predicted Scaffold-Compatible Sequence Variation in the Triple-Hairpin Structure of Human Immunodeficiency Virus Type 1 gp41 with Patient Data

2002 ◽  
Vol 76 (15) ◽  
pp. 7595-7606 ◽  
Author(s):  
Nathalie Boutonnet ◽  
Wouter Janssens ◽  
Carlo Boutton ◽  
Jean-Luc Verschelde ◽  
Leo Heyndrickx ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequence Variation ◽  
Single Point ◽  
Point Mutations ◽  
Hairpin Structure ◽  
Single Amino Acid ◽  
Immunodeficiency Virus

ABSTRACT It has been proposed that the ectodomain of human immunodeficiency virus type 1 (HIV-1) gp41 (e-gp41), involved in HIV entry into the target cell, exists in at least two conformations, a pre-hairpin intermediate and a fusion-active hairpin structure. To obtain more information on the structure-sequence relationship in e-gp41, we performed in silico a full single-amino-acid substitution analysis, resulting in a Fold Compatible Database (FCD) for each conformation. The FCD contains for each residue position in a given protein a list of values assessing the energetic compatibility (ECO) of each of the 20 natural amino acids at that position. Our results suggest that FCD predictions are in good agreement with the sequence variation observed for well-validated e-gp41 sequences. The data show that at a minECO threshold value of 5 kcal/mol, about 90% of the observed patient sequence variation is encompassed by the FCD predictions. Some inconsistent FCD predictions at N-helix positions packing against residues of the C helix suggest that packing of both peptides may involve some flexibility and may be attributed to an altered orientation of the C-helical domain versus the N-helical region. The permissiveness of sequence variation in the C helices is in agreement with FCD predictions. Comparison of N-core and triple-hairpin FCDs suggests that the N helices may impose more constraints on sequence variation than the C helices. Although the observed sequences of e-gp41 contain many multiple mutations, our method, which is based on single-point mutations, can predict the natural sequence variability of e-gp41 very well.

Towards a Drosophila model of Hutchinson–Gilford progeria syndrome

2008 ◽  
Vol 36 (6) ◽  
pp. 1389-1392 ◽  
Author(s):  
Gemma S. Beard ◽  
Joanna M. Bridger ◽  
Ian R. Kill ◽  
David R.P. Tree
Keyword(s):  
Drosophila Melanogaster ◽  
Premature Aging ◽  
Lamin A ◽  
Wild Type ◽  
Drosophila Model ◽  
Numerous Cell ◽  
Cellular Abnormalities ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Adult Drosophila

The laminopathy Hutchinson–Gilford progeria syndrome (HGPS) is caused by the mutant lamin A protein progerin and leads to premature aging of affected children. Despite numerous cell biological and biochemical insights into the basis for the cellular abnormalities seen in HGPS, the mechanism linking progerin to the organismal phenotype is not fully understood. To begin to address the mechanism behind HGPS using Drosophila melanogaster, we have ectopically expressed progerin and lamin A. We found that ectopic progerin and lamin A phenocopy several effects of laminopathies in developing and adult Drosophila, but that progerin causes a stronger phenotype than wild-type lamin A.

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