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Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy is one of the subtypes of immune-mediated necrotizing myopathy. Anti-HMGCR antibodies induce complement activation,subsequently resulting in myofiber necrosis,regeneration with autophagy abnormalities and mitochondrial changes. The age of onset is from children to adulthood. Some patients have a history of exposure to statins. Most patients are subacute onset. The patients with chronic progressive process, are more like muscular dystrophy. The main symptoms are proximal symmetrical weakness of limbs and usually accompanied with extra-muscle symptoms. The MRI showed muscle edema in all patients and fatty infiltrates in some patients. Myositis-specific auto-antibodies and muscle biopsies play key roles in diagnosis of HMGCR myopathy. Corticosteroids and immunosuppressants were first line therapy. Pediatric patients or patients with chronic course are usually refractory, and the efficacy of different combinations of immunosuppressants needs to be further investigated.
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Objective:To explore clinical characteristics and treatment of pediatric anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody-positive myopathy.Methods:Two cases of pediatric anti-HMGCR antibody-positive myopathy admitted to the Department of Neurology, Shenzhen Children′s Hospital from January to July 2020 were retrospectively analyzed for their clinical manifestations, creatine kinase (CK), myositis autoantibody, electromyography (EMG), muscle pathology, muscle magnetic resonance imaging (MRI), and treatment information.Results:Both of them were female cases.Case 1 was 3 years and 11 months old and case 2 was 7 years and 9 months old.They used to be healthy without history of statin use.Case 1 showed chronic onset of the disease, and case 2 had a subacute onset.The main clinical manifestations were progressive symmetric proximal muscle weakness accompanied by myalgia.Case 1 developed skin rash but case 2 did not.Significantly increased CK level was detected in both of them, which increased by 27.3-48.0 and 66.7-77.4 times of the upper limit before treatment in case 1 and case 2, respectively.They were diagnosed as muscular dystrophy at the early stage.EMG results suggested myogenic injuries in 2 cases, and muscle MRI showed extensive muscle edema.The muscle pathology of the 2 cases suggested muscle necrosis with a small amount of inflammatory cell infiltration.After diagnosis, both of them were treated with Methylprednisolone combined with intravenous immunoglobulin.CK decreased significantly but remained high, and muscle weakness was improved but did not return to normal.Oral Prednisone was given after discharge and case 2 was additionally medicated with azathioprine.Conclusions:Compared with adult patients, the clinical characteristics of pediatric anti-HMGCR antibody-positive myopathy are mostly similar.However, children patients usually have no history of statins and are more difficult to treat, less effective and worse prognosis.In addition, children patients are more likely to be diagnosed with " muscular dystrophy" at the beginning of illness.Therefore, idiopathic myositis autoantibody should be examined to confirm the diagnosis for children suspected to be " muscular dystrophy" but not confirmed by genetic examination.
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Objective:To determine the clinical, pathological and imaging phenotypes of pediatric patients with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy to explore its diagnostic strategies.Methods:The clinical features of 10 pediatric patients with anti-HMGCR myopathy in the Department of Neurology, Peking University First Hospital from July 2014 to July 2021 were collected. Muscle biopsies were performed in all patients, with histological, enzymatic histochemical and immunohistochemical staining.Results:The male to female ratio was 6∶4, the age of onset was 3-16 (8.3±3.7) years, 2 cases had subacute onset, and 8 cases experienced chronic progressive onset. All patients presented with neck and proximal muscular weakness of all limbs. Skin rash was observed in 2 cases. Serum creatine kinase was 998-27 981 U/L. The electromyography results were available from 6 cases, who experienced myogenic changes. The muscle magnetic resonance imaging was performed in 5 cases and revealed muscle edema predominantly in posterior compartment of thigh, with mild fatty infiltrate in 2 cases. An initial diagnosis was limb-girdle muscular dystrophy in 7 cases, but with subsequently negative genetic testing. Muscle biopsies revealed scattered necrotic fibers and regenerating fibers, complement deposition in sarcolemma basement-membrane areas of non-necrotic fibers and a few of lymphocyte infiltrate in all specimens. Moreover, a high frequency of major histocompatibility complex Ⅰ expression in muscle fibers was observed in 9 cases, proliferation of connective tissue of endomysium in 8 cases, muscle fiber hypertrophy in 4 cases and vacuoles in 2 cases.Conclusions:Pediatric anti-HMGCR myopathy is frequently misdiagnosed as muscular dystrophy. Systematic consideration of anti-HMGCR myopathy and testing for myositis specific antibody in children with genetically unconfirmed muscular dystrophy may help the differential diagnosis.
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@#AIM:To investigate the association between single nucleotide polymorphisms(SNPs)of Lanosterol synthase(LSS)and 3-Hydroxy-3-methylglutaryl coenzyme A reductase(HMGCR)genes and age-related cataract(ARC)risks. <p>METHODS: This was a case-control study. The SNPs of the genes were assayed with TaqMan RT-PCR genotyping. The qRT-PCR was used to detect the <i>LSS</i> mRNA levels of lens epithelial cells(LECs)in individuals. The Chi-square test was used to compare differences of each SNPs between ARCs and controls and to calculate the odds ratio. <p>RESULTS: We found that <i>LSS</i>-rs2968 of ARCs was different from controls(<i>P</i>=0.018), but the significance was lost after Bonferroni correction(<i>P</i>=0.072). We then further performed stratification analysis and found that <i>LSS</i>-rs2968 A allele was associated with nuclear type of ARC risk in Chinese population(<i>P</i>=0.003), and the significances still existed after Bonferroni correction(<i>P</i>=0.012). Consequently, we found that the <i>LSS</i> mRNA levels was lower in LECs of all subtypes of ARC group than that of control group(<i>P</i><0.05). <p>CONCLUSION: <i>LSS</i>-rs2968 A allele might plays a role in the formation and development of nuclear type of ARC risk in Jiangsu population.
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3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the first rate-limiting enzyme of terpenoid biosynthesis in the mevalonic acid pathway (MVA) pathway. It is an important regulatory site in terpenoids metabolism pathway in the cytoplasm. According to the transcriptome database of Cinnamomum camphora, two HMGRs named CcHMGR1 (GenBank: MN163055) and CcHMGR2 (GenBank: MN163056) were cloned by cDNA from C. camphora. The ORF of CcHMGR1 and CcHMGR2 is composed of 1 689 bp and 1 683 bp, respectively, encoding 562 and 560 amino acids. The bioinformatics analysis of CcHMGR1 and CcHMGR2 indicated that the molecular weight of the encoded protein is 59.819 kDa and 59.397 kDa, with a theoretically isoelectric point of 8.20 and 8.61, respectively. There are 2 transmembrane structures without signal peptide existing in the encoded amino acid of CcHMGRs. The analysis of sequence alignment and phylogenetic tree showed that theCcHMGRs belonged to the HMGR family. The camphor is divided into five chemitypes, according to the main chemical compoundsin C. camphora. The results of the real time PCR indicated that the expression level of CcHMGRs in Cineol type was higher than that in Linalool type, iso-nerolidol type, Camphor type and Borneol type. CcHMGRs expressed highest in roots and lowest in branches. In this study, the cDNA full length of CcHMGRs were cloned from C. camphora for the first time. Our results revealed that the expression level of CcHMGRs were different among five chemical types and different plant tissues, and the research provides foundation for further study of the terpenoids biosynthetic pathway in C. camphora.
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Objective: To clone the full-length cDNA of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) from Aquilaria sinensis (AsHMGR1) and to analyze its expression profile in different tissues and in response to different treatments. HMGR is the first rate-limiting enzyme for sesquiterpene synthesis in the mevalonate pathway. Methods: RT-PCR and RACE were used to clone the full-length cDNA of HMGR from A. sinensis based on the conserved HMGR gene fragments. The bioinformatic analysis was performed on its nucleic acid and protein sequence. The expression profile of AsHMGR1 in different tissues and in response to different treatments was analyzed by quantitative RT-PCR. Results: The full-length AsHMGR1 cDNA was 2026 bp, containing a 1719 bp open reading frame which encoded a protein of 572 amino acids. Amino acid sequence homology alignment and phylogenetic analysis demonstrated that AsHMGR1 belonged to the HMGR gene family. The detection of tissue expression patterns showed that AsHMGR1 was mainly expressed in the stem, followed by roots and branches. AsHMGR1 could be stimulated by methyl jasmonate and H2O2 to varying degrees in a time-dependent manner. Conclusion: These data will provide a foundation for further investigation on AsHMGR1 functions and regulatory mechanisms in sesquiterpene synthesis in A. sinensis. © 2013 Tianjin Press of Chinese Herbal Medicines.
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Objective: Panax notoginseng is an important medicinal plant and its secondary metabolites, P. notoginseng saponins (PNS), synthesized by the mevalonate pathway are the active ingredients. The study on the gene of the key enzyme 3-hydroxy-3- methylglutaryl-coenzyme-A reductases (HMGR) in the mevalonate pathway is helpful for the regulation of PNS syntheses. Methods: The primers were designed according to P. ginseng HMGR (accession number: GU565097.1) from NCBI. Total RNA was extracted from the callus of P. notoginseng. The fragment of HMGR gene was amplified by reverse transcription PCR technology and analyzed. Results: Sequence analysis showed that the cDNA sequence of obtained fragment (PnHMGR) was 1 893 bp, containing an ORF spaning 1 725 bp, and exhibited 98%, 93%, and 80% sequence identity with HMGR in P. ginseng, Eleutherococcus senticosus, and Eucommia ulmoides. The cDNA was a new one as searching in the Genbank. The bioinformatic analysis showed that PnHMGR-encoding protein contained two transmembrane regions and the HMGR catalytic domain, without signal peptide. The expression level of PnHMGR was the highest when the callus of P. notoginseng has grown for 30 d. Conclusion: It is the first time to report HMGR gene isolated from P. notoginseng. The results will provide a groundwork for exploring the molecular function of PnHMGR involved in PNS biosynthesis based on the synthetic biology of P. notoginseng.
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OBJECTIVE: The aim of this study is to compare cholesterol lowering effects of low dose 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in Korean patients. METHODS: A total of 909 consecutive patients were enrolled prospectively according to the criteria of National Cholesterol Education Program guidelines. Lipid profiles were obtained before and 2 months after statin therapy. RESULTS: Atorvastatin 10 mg (n=260), lovastatin 20 mg (n=145), pitavastatin 2 mg (n=80), pravastatin 20 mg (n=28), rosuvastatin 5 mg (n=145), and simvastatin 20 mg (n=208) reduced low density lipoprotein (LDL) cholesterol by -41.8+/-11.0%, -33.8+/-12.8%, -39.3+/-10.8%, -31.5+/-8.9%, -48.8+/-12.3%, and -42.8+/-13.5%, respectively. LDL cholesterol less than 130 mg/dL was achieved in 90.3%, 76.9%, 88.5%, 85.2%, 97.2%, and 94.2%, respectively. The reduction of LDL cholesterol by 30% or more was obtained in 84.4%, 60.7%, 81.6%, 63.0%, 93.0%, and 83.5%, respectively. LDL cholesterol less than 70 mg/dL or the reduction by 50% or more was observed in a small portion of patients and was variable according to the different types of statins. CONCLUSION: A low dose statin was enough to manage dyslipidemia in most Korean patients with low to moderate risks and was even effective in a subpopulation of high risk patients.
Subject(s)
Humans , Cholesterol , Cholesterol, LDL , Coenzyme A , Dyslipidemias , Education , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Lipoproteins , Lovastatin , Oxidoreductases , Pravastatin , Prospective Studies , Simvastatin , Atorvastatin , Rosuvastatin CalciumABSTRACT
Objective To clone and sequence cDNA encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMGR) from Atractylodes lancea.Methods The cDNA,encoding HMGR in A.lancea,was amplified by RACE strategy with the cDNA of the total RNA of young leaves as the template.The partial fragments of HMGR were cloned and sequenced.Results The analysis results revealed that the conserved fragments were 458 bp.At the same time,the two fragments had been obtained 84.28% identification in nucleotide acid and 92.11% identification in corresponding amino acid,named as HMGRcr1 and HMGRcr2,respectively.It was deduced that they may be members of the HMGR gene family in A.lancea.Sequencing analysis showed that HMGRcr1 and HMGRcr2 had high identity with HMGR from other plants.Conclusion The cDNA encoding HMGR from A.lancea is cloned and reported for the first time.The work will provided a foundation for exploring the mechanism of terpenes biosynthesis and application to the other medicinal plants.