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(A) General appearance of the patient with characteristic prematurely aged appearance, retarded growth. (B) Lateral and top view of the head showing macrocephaly, alopecia, prominent scalp veins.
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Hutchinson-Gilford progeria syndrome (HGPS) is a rare condition originally described by Hutchinson in 1886. Death result from cardiac complications in the majority of cases and usually occurs at average age of thirteen years. A 4-yr old boy had typical clinical findings such as short stature, craniofacial disproportion, alopecia, prominent scalp ve...
Citations
... A range of early-to late-stage plaques and complex calcified lesions have been identified within coronary arteries in postmortem studies (1), and carotid sonography has found atherosclerotic plaques in the cervical arteries (7,8). To the best of our knowledge, only one case of HGPS has been confirmed by genetic analysis in Korea (9), and the patient showed a hypertrophied internal layer at the internal carotid artery (ICA) on carotid Doppler sonography, suggesting atherosclerosis. ...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, progressive, premature aging syndrome with
early morbidity due to cardiovascular and cerebrovascular diseases. Clinical symptoms are very diverse,
including non-specific symptoms such as growth retardation, scleroderma, alopecia, and osteoporosis,
as well as hypertension and cardiovascular diseases that occur in childhood and adolescence
due to accelerated vascular aging. In patients with HGPS, MR angiography is recommended for
early diagnosis of asymptomatic stroke or vascular changes and to assess increased risk of cerebrovascular
disease. We report the second domestic case of HGPS confirmed by genetic analysis in a
5-year-old child with typical clinical features, and the first English case report in Korea to present
brain MR angiography findings.
... Although the authors focused on scleroderma-like manifestations found in Mucolipidosis type III (pseudo-Hurler polydystrophy), it would have also been useful to mention other genes associated with a scleroderma-like phenotype in their study discussion. Some examples are listed below: FAM 111B gene for scleroderma and multisystemic fibrosis-like hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) [2] RECQL4 gene for Rothmund Thomson Syndrome (RTS) [3], WRN gene for Werner syndrome (WS) [4] LMNA gene in Hutchinson-Gilford progeria syndrome (HGPS) [5] Finally, considering the multifactorial etiology of fibrosis, it would be interesting to see how the new gene (GNPTG) compares to other genes involved in scleroderma-like diseases such as FAM 111B (POIKTMP), RECLQL4 (RTS), WRN (WS) and LMNA (HGPS); and if there are possible gene interactions, considering the similarities in the phenotype produced. ...
... Abnormal cellular structures arising from proteins expressed by mutant genes can negatively impact tissue and organ function predisposing individuals inheriting genetic mutations to PLOS ONE | https://doi.org/10.1371/journal.pone.0188256 November 17, 2017 1 / 17 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 disease [1][2][3]. One particularly severe example is Hutchinson-Gilford Progeria Syndrome (HGPS) in which a mutation in the Lamin A/C (LMNA) gene causes premature aging up to seven times faster than normal, usually culminating in death due to cardiovascular complications [1]. ...
... November 17, 2017 1 / 17 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 disease [1][2][3]. One particularly severe example is Hutchinson-Gilford Progeria Syndrome (HGPS) in which a mutation in the Lamin A/C (LMNA) gene causes premature aging up to seven times faster than normal, usually culminating in death due to cardiovascular complications [1]. Other types of LMNA gene mutations are associated with a range of heart disease symptoms including cardiomyopathy, heart failure, and arrhythmia [2,4,5]. ...
Nuclear shape defects are a distinguishing characteristic in laminopathies, cancers, and other pathologies. Correlating these defects to the symptoms, mechanisms, and progression of disease requires unbiased, quantitative, and high-throughput means of quantifying nuclear morphology. To accomplish this, we developed a method of automatically segmenting fluorescently stained nuclei in 2D microscopy images and then classifying them as normal or dysmorphic based on three geometric features of the nucleus using a package of Matlab codes. As a test case, cultured skin-fibroblast nuclei of individuals possessing LMNA splice-site mutation (c.357-2A>G), LMNA nonsense mutation (c.736 C>T, pQ246X) in exon 4, LMNA missense mutation (c.1003C>T, pR335W) in exon 6, Hutchinson-Gilford Progeria Syndrome, and no LMNA mutations were analyzed. For each cell type, the percentage of dysmorphic nuclei, and other morphological features such as average nuclear area and average eccentricity were obtained. Compared to blind observers, our procedure implemented in Matlab codes possessed similar accuracy to manual counting of dysmorphic nuclei while being significantly more consistent. The automatic quantification of nuclear defects revealed a correlation between in vitro results and age of patients for initial symptom onset. Our results demonstrate the method’s utility in experimental studies of diseases affecting nuclear shape through automated, unbiased, and accurate identification of dysmorphic nuclei.
... More specifically, the point mutations that occur in the lamin A/C are vital in demonstrating the disease [19,21]. Dominant negative form of lamin A protein is produced as a consequence of the mutation G608G (GGC to GGT) within the exon 11 of lamin [22][23][24]. This mutation results in the formation of cryptic splice site subsequently causing the cleavage of 50 amino acid residues in the C-terminus of lamin A [19,25,26] and thus forms a protein named progerin with a distorted nucleus. ...
Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski’s rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.
... Recent clinical studies show that FTIs can be used for the treatment of Progeria, which is also known as Hutchinson-Gilford Progeria Syndrome (HGPS), a rare, fatal genetic disease characterized by an appearance of accelerated aging in children and originally described by Hutchinson in 1886 [52]. It is caused by de novo dominant mutations in lamin A. Lamin A is synthesized as a precursor, prelamin A, which has a CAAX motif at its carboxyl terminus. ...
Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn2+ ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral arterial stiffness, bone structure and audiological status in the patients. Other important FTIs such as BMS-214662, LB42908, LB42708, etc are under clinical studies for the treatment of various cancers. This review concluded that the quantitative structural analysis report with an elaborative study on the natural product compounds provides ideas for development of novel molecules for the FTase inhibitory activity. The fragment based analysis is also needed to select the substituents, which provides significant inhibitory activities and can also have good pharmacokinetic properties in the clinical studies.
... [5][6][7] Additional clinical HGPS manifestations include dermal and bone abnormalities, alopecia, and joint contractures. 5,[8][9][10][11][12][13][14][15][16] Moreover, the aortas and aortic valves of HGPS patients are excessively calcified, 10-12 and arteries from old transgenic mice carrying a human bacterial artificial chromosome that harbors the common HGPS mutation accumulate calcium deposits that are absent in age-matched controls. 17 However, the mechanisms underlying excessive vascular calcification in HGPS remain unexplored. ...
Background:
Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly of myocardial infarction or stroke. The goal of this study was to investigate mechanisms that cause excessive vascular calcification in HGPS.
Methods and results:
We performed expression and functional studies in wild-type mice and knock-in Lmna(G609G/+) mice expressing progerin, which mimic the main clinical manifestations of HGPS. Lmna(G609G/+) mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells from these progeroid animals had an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing vascular smooth muscle cells is associated with increased expression and activity of tissue-nonspecific alkaline phosphatase and mitochondrial dysfunction, which leads to reduced ATP synthesis. Accordingly, Lmna(G609G/+) vascular smooth muscle cells are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of Lmna(G609G/+) mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice.
Conclusions:
Excessive vascular calcification in Lmna(G609G) mice is caused by reduced extracellular accumulation of pyrophosphate that results from increased tissue-nonspecific alkaline phosphatase activity and diminished ATP availability caused by mitochondrial dysfunction in vascular smooth muscle cells. Excessive calcification is ameliorated on pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, because progerin progressively accumulates in the vascular tissue of individuals without HGPS.
Craniosynostosis (CS) refers to the group of craniofacial malformations characterized by the premature closure of one or more cranial sutures. The disorder is clinically and genetically heterogeneous and occurs usually as an isolated trait, but can also be syndromic. In 30–60% of patients, CS is caused by known genetic factors; however, in the rest of the cases, causative molecular lesions remain unknown. In this paper, we report on a sporadic male patient affected by complex CS (metopic and unilateral lambdoid synostosis), muscular hypotonia, psychomotor retardation, and facial dysmorphism. Since a subset of CS results from submicroscopic chromosomal aberrations, we performed array comparative genomic hybridization (array CGH) in order to identify possibly causative copy-number variation. Array CGH followed by breakpoint sequencing revealed a previously unreported de novo 1.26 Mb duplication at chromosome 1q22-q23.1 that encompassed two genes involved in osteoblast differentiation: BGLAP, encoding osteocalcin (OCN), and LMNA, encoding lamin A/C. OCN is a major component of bone extracellular matrix and a marker of osteogenesis, whereas mutations in LMNA cause several genetic disorders called laminopathies, including mandibuloacral dysostosis (MAD) that manifests with low bone mass, severe bone deformities, and delayed closure of the cranial sutures. Since LMNA and BGLAP overexpression promote osteoblast differentiation and calcification, phenotype of our patient may result from misexpression of the genes. Based on our findings, we hypothesize that both LMNA and BGLAP may be implicated in the pathogenesis of CS in humans. However, further studies are needed to establish the exact pathomechanism underlying development of this defect.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that shows a characteristic progeria phenotype. We conducted a questionnaire survey of 1173 tertiary hospitals in Japan and reviewed the academic reports, to identify the characteristics of Asian patients with classical HGPS. As a result, four Japanese patients were identified; this was estimated to account for approximately two-third of the prevalence in Japan. Three Asian patients who had definitively been diagnosed with classical HGPS were identified in the literature; in total, the clinical characteristics of seven patients were evaluated. Most of the clinical phenotypes of Asian patients were essentially similar to those of patients of other ethnicities, such as sclerodermatous skin, growth failure, loss of scalp hair or severe complications of cardiovascular and cerebral ischemic disease. In conclusion, to circumvent or minimalize severe vascular complication, an early diagnosis, careful observation and, promisingly, new intervention with farnesylation inhibitors may improve the prognosis of classical HGPS patients.Journal of Human Genetics advance online publication, 7 September 2017; doi:10.1038/jhg.2017.90.
