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Twists and turns of the genetic story of mevalonate kinase-associated diseases:A review

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Genes & diseases 2022年第4期9卷 1000-1007页

作者： Isabelle Touitou IRMB Univ MontpellierINSERMMontpellier 34090France Department of Medical genetics Rare Diseases and Personalized MedicineRare and Autoinflammatory Diseases UnitCeRéMAIACHUMontpellier 34000France

Mevalonate kinase (MK)-associated diseases encompass a broad spectrum of rare auto-inflammatory conditions, all resulting from pathogenic variants in the mevalonate kinase gene (MVK). Their clinical manifestations are highly variable, ranging from more or less serious systemic disorders, such as hereditary recurrent fevers, to purely localized pathologies such as porokeratosis. The oldest condition identified as linked to this gene is a metabolic disease called mevalonic aciduria, and the most recent is disseminated superficial actinic porokeratosis, a disease limited to the skin. The modes of inheritance of MK-associated diseases also diverge among the different subtypes: recessive for the systemic subtypes and dominant with a post-zygotic somatic genetic alteration for MVK-associated porokeratosis. This review quickly retraces the historical steps that led to the description of the various MK-associated disease phenotypes and to a better understanding of their pathophysiology, then summarizes and compares the different genetic mechanisms involved in this group of disorders, and finally discusses the diverse causes that could underlie this phenotypic heterogeneity.

关键词： Autoinflammatory disease Genetic Disease Meval onate kinase deficiency Porokeratosis Subtypes

Progress and challenges in CRISPR-mediated therapeutic genome editing for monogenic diseases

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The Journal of Biomedical Research 2021年第2期35卷 148-162页

作者： Colin T.Konishi Chengzu Long Leon H.Charney Division of Cardiology New York University Grossman School of MedicineNew YorkNY 10016USA Helen and Martin Kimmel Center for Stem Cell Biology New York University Grossman School of MedicineNew YorkNY 10016USA Department of Neurology New York University Grossman School of MedicineNew YorkNY 10016USA Department of Neuroscience and Physiology New York University Grossman School of MedicineNew YorkNY 10016USA

There are an estimated 10000 monogenic diseases affecting tens of millions of individuals worldwide.The application of CRISPR/Cas genome editing tools to treat monogenic diseases is an emerging strategy with the potential to generate personalized treatment approaches for these patients.CRISPR/Cas-based systems are programmable and sequence-specific genome editing tools with the capacity to generate base pair resolution manipulations to DNA or RNA.The complexity of genomic insults resulting in heritable disease requires patientspecific genome editing strategies with consideration of DNA repair pathways,and CRISPR/Cas systems of different types,species,and those with additional enzymatic capacity and/or delivery methods.In this review we aim to discuss broad and multifaceted therapeutic applications of CRISPR/Cas gene editing systems including in harnessing of homology directed repair,non-homologous end joining,microhomology-mediated end joining,and base editing to permanently correct diverse monogenic diseases.

关键词： gene editing CRISPR-associated protein 9 CRISPR-Cas system Genetic Disease medical genetics genetic therapy

Exploring noncoding variants in Genetic Diseases:from detection to functional insights

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Journal of genetics and Genomics 2024年第2期51卷 111-132页

作者： Ke Wu Fengxiao Bu Yang Wu Gen Zhang Xin Wang Shunmin He Mo-Fang Liu Runsheng Chen Huijun Yuan Institute of Rare diseases West China Hospital of Sichuan UniversityChengduSichuan 610041China Key Laboratory of Systems Health Science of Zhejiang Province School of Life ScienceHangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhouZhejiang 310024China Key Laboratory of RNA Biology Center for Big Data Research in HealthInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China State Key Laboratory of Molecular Biology State Key Laboratory of Cell BiologyShanghai Key Laboratory of Molecular AndrologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceChinese Academy of SciencesShanghai 200031China

Previous studies on Genetic Diseases predominantly focused on protein-coding variations, overlooking the vast noncoding regions in the human genome. The development of high-throughput sequencing technologies and functional genomics tools has enabled the systematic identification of functional noncoding variants. These variants can impact gene expression, regulation, and chromatin conformation, thereby contributing to disease pathogenesis. Understanding the mechanisms that underlie the impact of noncoding variants on Genetic Diseases is indispensable for the development of precisely targeted therapies and the implementation of personalized medicine strategies. The intricacies of noncoding regions introduce a multitude of challenges and research opportunities. In this review, we introduce a spectrum of noncoding variants involved in Genetic Diseases, along with research strategies and advanced technologies for their precise identification and in-depth understanding of the complexity of the noncoding genome. We will delve into the research challenges and propose potential solutions for unraveling the genetic basis of rare and complex diseases.

关键词： Noncoding variation Genetic Disease Research approach Challenge

Juvenile hemochromatosis:HAMP mutation and severe iron overload treated with phlebotomies and deferasirox

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World Journal of Clinical Cases 2017年第10期5卷 381-383页

作者： Manuel A Lescano Letícia C Tavares Paulo C J L Santos Institute of Digestive Tract of Southwestern Bahia Laboratory of genetics and Molecular Cardiology Heart Institute (InCor)University of Sao Paulo Medical School

Juvenile hemochromatosis(JH) is a rare condition classified as an autosomal recessive disorder that leads to severe iron absorption. JH usually affects people under the age of 30 and presents symptoms such as chronic liver damage,hypogonadotropic hypogonadism,cardiac diseases and endocrine dysfunctions. The present case reports a 29-year-old Brazilian woman with JH condition due to HAMP mutation(g.47G>A),treated with phlebotomies and deferasirox. She presented symptoms such as weakness,skin hyperpigmentation,joint pain in the shoulders and hands and amenorrhea. First laboratory tests showed altered biochemical parameters [serum ferritin(SF): 5696 ng/mL,transferrin saturation(TS): 85%]. After sessions of phlebotomies(450 mL every 15 d),the patient presented partial symptomatic improvements and biochemical parameters(SF: 1000 ng/mL,Hb: 11 g/dL). One year later,deferasirox(15 mg/kg per day) was introduced to the treatment,and the patient showed total symptomatic improvement,with significant clearing of the skin,SF: 169 ng/mL,and TS: 50%. Furthermore,after the combined deferasirox-phlebotomy therapy,magnetic resonance imaging measurements revealed normalized level for liver iron(30 μmol/g; reference value < 36 μmol/g). In conclusion,combined deferasirox-phlebotomy treatment was able to normalize iron levels and improve symptoms.

关键词： Genetic Disease Juvenile hemochromatosis HAMP gene Mutation Iron chelation

Linear porokeratosis of the foot with dermoscopic manifestations: A case report

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World Journal of Clinical Cases 2022年第31期10卷 11585-11589页

作者： Jing Yang Yi-Qing Du Xiao-Ya Fang Bo Li Zhi-Qin Xi Wen-Li Feng Department of Dermatology The Second Hospital of Shanxi Medical UniversityTaiyuan 030001Shanxi ProvinceChina Department of Dermatology Gaoping City People’s HospitalGaoping 048400Shanxi ProvinceChina

BACKGROUND Porokeratosis(PK)is a common autosomal dominant chronic progressive dyskeratosis with various clinical manifestations.Based on clinical manifestations,porokeratosis can be classified as porokeratosis of mibelli,disseminated superficial porokeratosis,disseminated superficial actinic porokeratosis,linear porokeratosis(LP),porokeratosis palmaris et plantaris disseminata,porokeratosis punctata,popular PK,hyperkeratosis PK,inflammatory PK,verrucous PK,and mixed types.We report a case of LP in a child and describe its dermoscopic findings.CASE SUMMARY Linear porokeratosis is a rare PK.The patient presented with unilateral keratinizing maculopapular rash of the foot in childhood.The patient underwent skin pathology and dermoscopy,and was treated with liquid nitrogen freezing and topical drugs.CONCLUSION From this case we take-away that LP is a rare disease,by the dermoscopic we can identify it.

关键词： Porokeratosis Dermoscope Linear porokeratosis Genetic Disease Chromosome Case report

Dissection of Developmental Mechanisms of Neurocristopathy in Waardenburg Syndrome and Piebaldism Mouse Models

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Dissection of Developmental Mechanisms of Neurocristopathy i...

Pterygium Popliteal Syndrome Concerning a Case in the Pediatric Surgery Department of the Donka National Hospital (Conakry CHU)

第二届全国发育生物学大会

作者： Ling Hou Developmental Cell Biology and disease Program Vision Science Research CenterWenzhou Medical University

Many human neurocristopathies include genetic defects in a number of syndromes,tumors,and dysmorphologies of neural crest stem cell derivatives during development.Mouse coat color mutations have long served as an excellent model for the study of neural crest stem cell developmental genetics.Due to shared embryonic origin of various tissues or to pleiotropic effects,these mutants also serve as human disease models for many aspects of studies including vision,hearing,craniofacial abnormalities,digestive disorders,and neural tube defects.In recent years a complex network of genes has been associated with pigmentation abnormalities and deafness in neurocristopathies resulting from NC stem cell-derived melanocyte deficiency.For example,Waardenburg syndrome(WS)can result from mutations either in SoxlO,Mitf or Ednrb and Piebaldism can result from mutations in Kit.Recent studies have revealed surprising new insights into how this network of interacting genes plays complex functional roles in melanocyte development.Currently,we are using Waardenburg Syndrome and Piebaldism mouse models to dissect developmental mechanisms of neurocristopathy.In this point of view,I will provide some of our findings and explore potential mechanisms by which this regulatory network of interacting genes may control melanocyte precursor differentiation.

关键词： Genetic Disease neural crest stem cell gene interaction melanocyte differentiation

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Open Journal of Pediatrics 2022年第1期12卷 162-169页

作者： Balla Keita Mamadou Alpha Toure Mohamed Lamie Sacko Mamadou Madiou Barry Mamadou Karamba Kaba Daniel Agbo-Panzo Pediatric Surgery Department CHU Donka Conakry Guinea Gamal Abdel Nasser University of Conakry Conakry Guinea Plastic Surgery Department CHU Donka Conakry Guinea

Introduction: Popliteal pterygium syndrome is a rare birth defect, combining craniofacial, genitourinary and musculoskeletal abnormalities. It is an autosomal dominant disease caused by a mutation in the IRF6 gene. We report in this observation the 1st Guinean case corrected by the surgical method as well as a review of the literature for a diagnostic and therapeutic approach. Patient and observation: We present the case of a 7-day old male newborn weighing 2700 g who was received for bilateral cleft lip and palate, lower lip fossa or sinuses, bilateral popliteal pterygium, and triangular skin fold above the hallux. The patient underwent several surgical procedures aimed at correcting these abnormalities. The correction of the pterygium of the lower limbs was ensured by excision of the fibrous band, the tenoplasty in z of the calcaneal tendon on the right side and the skin plasty in z in series then immobilized by plaster splints. The immediate postoperative follow-up was straightforward. Conclusion: Popliteal pterygium syndrome is a rare congenital malformation, the diagnosis is primarily clinical. Early soft tissue lengthening surgery and serial z-skin plasty provide better correction of the knee pterygium. Correct correction of facial abnormalities gives the child a better appearance. The management of this syndrome is multidisciplinary.

关键词： Popliteal Pterygium Congenital Malformation Genetic Disease Pediatric Surgery Multidisciplinary Team

Critical Role of Cystic Fibrosis Transmembrane Conductance Regulation(CFTR)in Female Reproduction

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皖南医学院学报 2003年第Z1期22卷 4-5页

作者： Hsiao Chang CHAN Epithelial Cell Biology Research Center Department of PhysiologyFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong

　　Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl- channel, mutations of which are responsible for defective Cl- and/or HCO-3 secretions seen in cystic fibrosis (CF), a common lethal Genetic Disease affecting most exocrine glands/organs, including the lungs, intestine, pancreas and reproductive tracts of both sexes.　　……

关键词： cystic fibrosis Genetic Disease

Value of predictive bioinformatics in inherited metabolic diseases

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World Journal of Medical genetics 2015年第3期5卷 46-51页

作者： David J Timson School of Biological Sciences and Institute for Global Food Security Queen’s University Belfast

Typically,inherited metabolic diseases arise from point mutations in genes encoding metabolic enzymes. Although some of these mutations directly affect amino acid residues in the active sites of these enzymes,the majority do not. It is now well accepted that the majority of these disease-associated mutations exert their effects through alteration of protein stability,which causes a reduction in enzymatic activity. This finding suggests a way to predict the severity of newly discovered mutations. In silico prediction of the effects of amino acid sequence alterations on protein stability often correlates with disease severity. However,no stability prediction tool is perfect and,in general,better results are obtained if the predictions from a variety of tools are combined and then interpreted. In addition to predicted alterations to stability,the degree of conservation of a particular residue can also be a factor which needs to be taken into account: alterations to highly conserved residues are more likely to be associated with severe forms of the disease. The approach has been successfully applied in a variety of inherited metabolic diseases,but further improvements are necessary to enable robust translation into clinically useful tools.

关键词： Genetic Disease Metabolism In silico method Protein stability disease-associated mutation