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Biomechanics and Modeling in... Aug 2023Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process...
Hutchinson-Gilford Progeria Syndrome results in rapid aging and severe cardiovascular sequelae that accelerate near end-of-life. We found a progressive disease process in proximal elastic arteries that was less evident in distal muscular arteries. Changes in aortic structure and function were then associated with changes in transcriptomics assessed via both bulk and single cell RNA sequencing, which suggested a novel sequence of progressive aortic disease: adverse extracellular matrix remodeling followed by mechanical stress-induced smooth muscle cell death, leading a subset of remnant smooth muscle cells to an osteochondrogenic phenotype that results in an accumulation of proteoglycans that thickens the aortic wall and increases pulse wave velocity, with late calcification exacerbating these effects. Increased central artery pulse wave velocity is known to drive left ventricular diastolic dysfunction, the primary diagnosis in progeria children. It appears that mechanical stresses above ~ 80 kPa initiate this progressive aortic disease process, explaining why elastic lamellar structures that are organized early in development under low wall stresses appear to be nearly normal whereas other medial constituents worsen progressively in adulthood. Mitigating early mechanical stress-driven smooth muscle cell loss/phenotypic modulation promises to have important cardiovascular implications in progeria patients.
Topics: Child; Humans; Progeria; Pulse Wave Analysis; Phenotype; Aortic Diseases; Myocytes, Smooth Muscle
PubMed: 37149823
DOI: 10.1007/s10237-023-01722-5 -
Journal of Developmental Biology Oct 2023The presence of farnesylated proteins at the inner nuclear membrane (INM), such as the Lamins or Kugelkern in , leads to specific changes in the nuclear morphology and...
The presence of farnesylated proteins at the inner nuclear membrane (INM), such as the Lamins or Kugelkern in , leads to specific changes in the nuclear morphology and accelerated ageing on the organismal level reminiscent of the Hutchinson-Gilford progeria syndrome (HGPS). Farnesyl transferase inhibitors (FTIs) can suppress the phenotypes of the nuclear morphology in cultured fibroblasts from HGPS patients and cultured cells overexpressing farnesylated INM proteins. Similarly, FTIs have been reported to suppress the shortened lifespan in model organisms. Here, we report an experimental system combining cell culture and flies for testing the activity of substances on the HGPS-like nuclear morphology and lifespan, with FTIs as an experimental example. Consistent with previous reports, we show that FTIs were able to ameliorate the nuclear phenotypes induced by the farnesylated nuclear proteins Progerin, Kugelkern, or truncated Lamin B in cultured cells. The subsequent validation in lifespan assays demonstrated the applicability of the experimental system: treating adult with the FTI ABT-100 reversed the nuclear phenotypes and extended the lifespan of experimentally induced short-lived flies. Since -expressing flies have a significantly shorter average lifespan, half the time is needed for testing substances in the lifespan assay.
PubMed: 37987370
DOI: 10.3390/jdb11040040 -
Pediatric Research Apr 2024Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. This study aims to...
BACKGROUND
Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. This study aims to investigate the epidemiological and genotypic characteristics of patients with HGPS/PL in China.
METHODS
Using a cross-sectional study design, general characteristics and genotypic data of 46 patients with HGPS/PL from 17 provinces in China were analyzed.
RESULTS
Among the 46 patients with HGPS/PL, 20 patients are HGPS, and the rest are PL; the identified total prevalence of HGPS/PL is 1/23 million. Among 42 patients with gene reports, 3 carried compound heterozygous mutations in the ZMPSTE24 while the other 39 carried LMNA mutations. Among PL, LMNA c.1579 C > T homozygous mutation was the most common. The onset of classic genotype HGPS is skin sclerosis in the first month after birth. The primary clinical manifestations of PL patients include skin abnormalities, growth retardation, and joint stiffness. The median age of onset for PL was 12 (6,12) months.
CONCLUSIONS
In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL were located in LMNA, and the rest in ZMPSTE24. Most patients of HGPS/PL have skin abnormalities as the earliest manifestation. Compared to PL, the classic genotype HGPS starts earlier.
IMPACT STATEMENT
Hutchinson-Gilford progeria syndrome (HGPS) and progeroid laminopathies (PL) are extremely rare genetic diseases with extremely poor prognoses. To date, there is a paucity of epidemiological data related to HGPS/PL in China. This study first examined the genotypic, phenotypic, and prevalence characteristics of 40-50% of the cases of HGPS/PL in mainland China through a collaborative international registry effort. In China, the identified total prevalence of HGPS/PL is 1/23 million. 92.8% of the genetic mutations of HGPS/PL are located in LMNA. LMNA c.1579 C > T homozygous mutations are the most common form of gene mutations among the Chinese PL population.
Topics: Humans; Progeria; China; Male; Female; Lamin Type A; Cross-Sectional Studies; Mutation; Child, Preschool; Infant; Prevalence; Child; Membrane Proteins; Metalloendopeptidases; Genotype; Adolescent; Laminopathies; Phenotype
PubMed: 38191824
DOI: 10.1038/s41390-023-02981-9 -
Human Molecular Genetics Sep 2023Mandibuloacral dysplasia type A (MADA) is a rare genetic progeroid syndrome associated with lamin A/C (LMNA) mutations. Pathogenic mutations of LMNA result in nuclear...
Mandibuloacral dysplasia type A (MADA) is a rare genetic progeroid syndrome associated with lamin A/C (LMNA) mutations. Pathogenic mutations of LMNA result in nuclear structural abnormalities, mesenchymal tissue damage and progeria phenotypes. However, it remains elusive how LMNA mutations cause mesenchymal-derived cell senescence and disease development. Here, we established an in vitro senescence model using induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) from MADA patients with homozygous LMNA p.R527C mutation. When expanded to passage 13 in vitro, R527C iMSCs exhibited marked senescence and attenuation of stemness potential, accompanied by immunophenotypic changes. Transcriptome and proteome analysis revealed that cell cycle, DNA replication, cell adhesion and inflammation might play important roles in senescence. In-depth evaluation of changes in extracellular vesicle (EV) derived iMSCs during senescence revealed that R527C iMSC-EVs could promote surrounding cell senescence by carrying pro-senescence microRNAs (miRNAs), including a novel miRNA called miR-311, which can serve as a new indicator for detecting chronic and acute mesenchymal stem cell (MSC) senescence and play a role in promoting senescence. Overall, this study advanced our understanding of the impact of LMNA mutations on MSC senescence and provided novel insights into MADA therapy as well as the link between chronic inflammation and aging development.
Topics: Humans; Induced Pluripotent Stem Cells; Multiomics; Biomarkers; MicroRNAs; Mesenchymal Stem Cells; Lamin Type A
PubMed: 37427980
DOI: 10.1093/hmg/ddad111 -
BioRxiv : the Preprint Server For... May 2024Bone fracture is one of the most globally prevalent injuries, with an estimated 189 million bone fractures occurring annually. Delayed union or nonunion occurs in up to...
BACKGROUND
Bone fracture is one of the most globally prevalent injuries, with an estimated 189 million bone fractures occurring annually. Delayed union or nonunion occurs in up to 15% of fractures and involves the interruption or complete failure of bone continuity following fracture. Preclinical testing is essential to support the translation of novel strategies to promote improved fracture repair treatment, but there is a paucity of small animal models that recapitulate clinical attributes associated with delayed fracture healing. This study explores whether the (Z24 ) knockout mouse model of Hutchinson-Gilford progeria syndrome presents with delayed fracture healing. Leveraging the previously characterized Z24 phenotype of genomic instability, epigenetic changes, and fragility, we hypothesize that these underlying alterations will lead to significantly delayed fracture healing relative to age-matched wild type (WT) controls.
METHODS
WT and Z24 mice received intramedullary fixed tibia fractures at ∼12 weeks of age. Mice were sacrificed throughout the time course of repair for the collection of organs that would provide information regarding the local (fracture callus, bone marrow, inguinal lymph nodes) versus peripheral (peripheral blood, contralateral tibia, abdominal organs) tissue microenvironments. Analyses of these specimens include histomorphometry, μCT, mechanical strength testing, protein quantification, gene expression analysis, flow cytometry for cellular senescence, and immunophenotyping.
RESULTS
Z24 mice demonstrated a significantly delayed rate of healing compared to WT mice with consistently smaller fracture calli containing higher proportion of cartilage and less bone after injury. Cellular senescence and pro-inflammatory cytokines were elevated in the Z24 mice before and after fracture. These mice further presented with a dysregulated immune system, exhibiting generally decreased lymphopoiesis and increased myelopoiesis locally in the bone marrow, with more naïve and less memory T cell but greater myeloid activation systemically in the peripheral blood. Surprisingly, the ipsilateral lymph nodes had increased T cell activation and other pro-inflammatory NK and myeloid cells, suggesting that elevated myeloid abundance and activation contributes to an injury-specific hyperactivation of T cells.
CONCLUSION
Taken together, these data establish the Z24 progeria mouse as a model of delayed fracture healing that exhibits decreased bone in the fracture callus, with weaker overall bone quality, immune dysregulation, and increased cellular senescence. Based on this mechanism for delayed healing, we propose this Z24 progeria mouse model could be useful in testing novel therapeutics that could address delayed healing.
THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE
This study employs a novel animal model for delayed fracture healing that researchers can use to screen fracture healing therapeutics to address the globally prevalent issue of aberrant fracture healing.
PubMed: 38854043
DOI: 10.1101/2024.05.29.596277 -
Frontiers in Cardiovascular Medicine 2024Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated...
Hutchinson-Gilford Progeria Syndrome (HGPS) is an ultra-rare genetic premature aging disease that is historically fatal in teenage years, secondary to severe accelerated atherosclerosis. The only approved treatment is the farnesyltransferase inhibitor lonafarnib, which improves vascular structure and function, extending average untreated lifespan of 14.5 years by 4.3 years (30%). With this longer lifespan, calcific aortic stenosis (AS) was identified as an emerging critical risk factor for cardiac death in older patients. Intervention to relieve critical AS has the potential for immediate improvement in healthspan and lifespan. However, HGPS patient-device size mismatch, pervasive peripheral arterial disease, skin and bone abnormalities, and lifelong failure to thrive present unique challenges to intervention. An international group of experts in HGPS, pediatric and adult cardiology, cardiac surgery, and pediatric critical care convened to identify strategies for successful treatment. Candidate procedures were evaluated by in-depth examination of 4 cases that typify HGPS clinical pathology. Modified transcatheter aortic valve replacement (TAVR) and left ventricular Apico-Aortic Conduit (AAC) placement were deemed high risk but viable options. Two cases received TAVR and 2 received AAC post-summit. Three were successful and 1 patient died perioperatively due to cardiovascular disease severity, highlighting the importance of intervention timing and comparative risk stratification. These breakthrough interventions for treating critical aortic stenosis in HGPS patients could rewrite the current clinical perspective on disease course by greatly improving late-stage quality of life and increasing lifespan. Expanding worldwide medical and surgical competency for this ultra-rare disease through expert information-sharing could have high impact on treatment success.
PubMed: 38725831
DOI: 10.3389/fcvm.2024.1356010 -
Journal of Neuroscience Research Jan 2024Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain...
Lamin A/C is involved in macrophage activation and premature aging, also known as progeria. As the resident macrophage in brain, overactivation of microglia causes brain inflammation, promoting aging and brain disease. In this study, we investigated the role of Lamin A/C in microglial activation and its impact on progeria using Lmna mice, primary microglia, Lmna knockout (Lmna-KO) and Lmna-knockdown (Lmna-KD) BV2 cell lines. We found that the microglial activation signatures, including cell proliferation, morphology changes, and proinflammatory cytokine secretion (IL-1β, IL-6, and TNF-α), were significantly suppressed in all Lamin A/C-deficient models when stimulated with LPS. TMT-based quantitative proteomic and bioinformatic analysis were further applied to explore the mechanism of Lamin A/C-regulated microglia activation from the proteome level. The results revealed that immune response and phagocytosis were impaired in Lmna microglia. Stat1 was identified as the hub protein in the mechanism by which Lamin A/C regulates microglial activation. Additionally, DNA replication, chromatin organization, and mRNA processing were also altered by Lamin A/C, with Ki67 fulfilling the main hub function. Lamin A/C is a mechanosensitive protein and, the immune- and proliferation-related biological processes are also regulated by mechanotransduction. We speculate that Lamin A/C-mediated mechanotransduction is required for microglial activation. Our study proposes a novel mechanism for microglial activation mediated by Lamin A/C.
Topics: Animals; Mice; Cell Proliferation; Lamin Type A; Macrophage Activation; Mechanotransduction, Cellular; Microglia; Phagocytosis; Progeria; Proteomics
PubMed: 38284866
DOI: 10.1002/jnr.25263 -
Journal of Radiology Case Reports Oct 2023Werner Syndrome is a rare autosomal recessive condition characterized by premature aging and increased risk of malignancies due to gene mutations associated with DNA...
Werner Syndrome is a rare autosomal recessive condition characterized by premature aging and increased risk of malignancies due to gene mutations associated with DNA stability. We present the first case report of a 29-year-old Hispanic female with WS diagnosed with breast cancer. Diagnostic mammography and ultrasound, breast MRI and PET examinations revealed two lesions biopsy proven as invasive ductal carcinoma. The patient underwent neoadjuvant chemotherapy and radical mastectomy. Recurrence occurred 10 months postoperatively with molecular analysis demonstrating TP53 mutations. The multifactorial assessment of breast cancer in this case study is crucial towards optimizing screening, diagnosis and management of this disease in patients with WS.
Topics: Adult; Female; Humans; Breast Neoplasms; Hispanic or Latino; Mastectomy; Mutation; Werner Syndrome; Werner Syndrome Helicase
PubMed: 38343885
DOI: 10.3941/jrcr.v17i8.5168 -
Heliyon Oct 2023Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease characterized by appearance of premature aging, including the skin, bones, heart, and blood...
An infant with congenital micrognathia and upper airway obstruction was diagnosed as Hutchinson-Gilford progeria syndrome caused by a novel LMNA mutation: Case report and literature review.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease characterized by appearance of premature aging, including the skin, bones, heart, and blood vessels caused by LMNA mutation. In this study, the patient presented with congenital micrognathia and progressively aggravated upper airway obstruction as the initial symptom, which required bilateral mandibular distraction osteogenesis (MDO) surgery intervention. This was not commonly described in the literature, and the primary clinical diagnosis of Pierre Robin sequence (PRS) was made. However, other clinical features included sclerotic skin, dry skin, growth failure, lipoatrophy, joint stiffness, prominent scalp veins, small ear lobes, hair loss, and craniofacial disproportion gradually emerged, the diagnosis of HGPS was preferred when the patient was 5 months old. The genetic testing result with a novel and de novo LMNA mutation (c.1968 + 3_1968+6delGAGT) further confirmed the diagnosis and expanded the clinical and mutational spectrum of HGPS. During the 12-month follow-up period after surgery, the patient no longer suffered dyspnea. Complications of other organs and systems have not happened at the moment. In addition, the pathogenesis, the role of LMNA gene mutation, the progress in clinical treatment, and breakthrough studies about genetic treatment in animals of HGPS are described in the literature review.
PubMed: 37916118
DOI: 10.1016/j.heliyon.2023.e20857 -
Endocrine Journal May 2024Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired...
Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.
PubMed: 38811207
DOI: 10.1507/endocrj.EJ24-0003