Clouston syndrome(OMIM#129500),also known as hidrotic ectodermal dysplasia type 2,is a rare autosomal dominant skin disorder.To date,four mutations in the GJB6 gene,G11R,V37E,A88V,and D50N,have been confirmed to cause...Clouston syndrome(OMIM#129500),also known as hidrotic ectodermal dysplasia type 2,is a rare autosomal dominant skin disorder.To date,four mutations in the GJB6 gene,G11R,V37E,A88V,and D50N,have been confirmed to cause this condition.In previous studies,the focus has been mainly on gene sequencing,and there has been a lack of research on clinical manifestations and pathogenesis.To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease,we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree.Detailed clinical examination included histopathology,hair microscopy,and scanning electron microscopy.We found a novel heterozygous missense variant(c.134G>C:p.G45A)for Clouston syndrome.We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients’hair under scanning electron microscopy.Our data reveal that a novel variant(c.134G>C:p.G45A)plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.展开更多
BACKGROUND Mutations in mitochondrial tRNA(mt-tRNA)genes that result in mitochondrial dysfunction play important roles in type 2 diabetes mellitus(T2DM).We previously reported a large Chinese pedigree with maternally ...BACKGROUND Mutations in mitochondrial tRNA(mt-tRNA)genes that result in mitochondrial dysfunction play important roles in type 2 diabetes mellitus(T2DM).We previously reported a large Chinese pedigree with maternally inherited T2DM that harbors novel mt-tRNA^(Trp)A5514G and tRNA^(Ser(AGY))C12237T variants,however,the effects of these mt-tRNA variants on T2DM progression are largely unknown.AIM To assess the potential pathogenicity of T2DM-associated m.A5514G and m.C12237T variants at genetic,molecular,and biochemical levels.METHODS Cytoplasmic hybrid(cybrid)cells carrying both m.A5514G and m.C12237T variants,and healthy control cells without these mitochondrial DNA(mtDNA)variants were generated using trans-mitochondrial technology.Mitochondrial features,including mt-tRNA steady-state level,levels of adenosine triphosphate(ATP),mitochondrial membrane potential(MMP),reactive oxygen species(ROS),mtDNA copy number,nicotinamide adenine dinucleotide(NAD+)/NADH ratio,enzymatic activities of respiratory chain complexes(RCCs),8-hydroxy-deoxyguanine(8-OhdG),malondialdehyde(MDA),and superoxide dismutase(SOD)were examined in cell lines with and without these mt-tRNA variants.RESULTS Compared with control cells,the m.A5514G variant caused an approximately 35%reduction in the steady-state level of mt-tRNA^(Trp)(P<0.0001);however,the m.C12237T variant did not affect the mt-tRNA^(Ser(AGY))steady-state level(P=0.5849).Biochemical analysis revealed that cells with both m.A5514G and m.C12237T variants exhibited more severe mitochondrial dysfunctions and elevated oxidative stress than control cells:ATP,MMP,NAD+/NADH ratio,enzyme activities of RCCs and SOD levels were markedly decreased in mutant cells(P<0.05 for all measures).By contrast,the levels of ROS,8-OhdG and MDA were significantly increased(P<0.05 for all measures),but mtDNA copy number was not affected by m.A5514G and m.C12237T variants(P=0.5942).CONCLUSION The m.A5514G variant impaired mt-tRNA^(Trp)metabolism,which subsequently caused mitochondrial dysfunction.The m.C12237T variant did not alter the steady-state level of mt-tRNA^(Ser(AGY)),indicating that it may be a modifier of the m.A5514G variant.The m.A5514G variant may exacerbate the pathogenesis and progression of T2DM in this Chinese pedigree.展开更多
目的:探讨新型冠状病毒奥米克戎株(Omicron Variant of Sars-Cov-2)对心脏外科围术期的相关影响。方法:选取自2022年12月12日至2023年1月19日期间,安贞医院心外科行心脏外科手术患者104例,收集患者一般临床资料、围手术期相关情况,根据...目的:探讨新型冠状病毒奥米克戎株(Omicron Variant of Sars-Cov-2)对心脏外科围术期的相关影响。方法:选取自2022年12月12日至2023年1月19日期间,安贞医院心外科行心脏外科手术患者104例,收集患者一般临床资料、围手术期相关情况,根据病原学转阴至手术日之间的天数,并根据天数分组,对新型冠状相关并发症进行回顾性研究,并对其相关性进行探讨。结果:本研究中共出现3例死亡患者,死亡原因2例是核酸复阳导致新型冠状病毒肺炎引发的低氧血症,1例是循环衰竭伴弥散性血管内凝血;转阴<1周组在在呼吸机使用时间及ICU停留时间方面显著长于其他各组;早期手术组呼吸机使用时间、ICU停留时间、二次气管插管及出现新型冠状病毒肺炎等方面均显著高于晚期手术组。结论:新型冠状奥米克戎株“阳康”早期内行心脏手术可能会影响预后;尤其是病原学转阴<14d患者在呼吸机使用时间、ICU停留时间、二次气管插管及出现新型冠状病毒肺炎等方面风险显著增加。展开更多
基金funded by Anhui Provincial Quality Engineering Project of Higher Education Institutions(No.2020jyxm0922)Natural Science Research Project of Higher Education Department of Anhui Province(No.KJ2021A0284)+1 种基金Fund of Anhui Provincial Institute of Translational Medicine(No.2021zhyx-C31)Research Foundation of Anhui Medical University(No.2020xkj154).
文摘Clouston syndrome(OMIM#129500),also known as hidrotic ectodermal dysplasia type 2,is a rare autosomal dominant skin disorder.To date,four mutations in the GJB6 gene,G11R,V37E,A88V,and D50N,have been confirmed to cause this condition.In previous studies,the focus has been mainly on gene sequencing,and there has been a lack of research on clinical manifestations and pathogenesis.To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease,we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree.Detailed clinical examination included histopathology,hair microscopy,and scanning electron microscopy.We found a novel heterozygous missense variant(c.134G>C:p.G45A)for Clouston syndrome.We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients’hair under scanning electron microscopy.Our data reveal that a novel variant(c.134G>C:p.G45A)plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.
基金Supported by the Hangzhou Joint Fund of the Zhejiang Provincial Natural Science Foundation of China,No.LHZY24H020002Hangzhou Municipal Health Commission,No.ZD20220010Quzhou Bureau of Science and Technology,No.2022K51.
文摘BACKGROUND Mutations in mitochondrial tRNA(mt-tRNA)genes that result in mitochondrial dysfunction play important roles in type 2 diabetes mellitus(T2DM).We previously reported a large Chinese pedigree with maternally inherited T2DM that harbors novel mt-tRNA^(Trp)A5514G and tRNA^(Ser(AGY))C12237T variants,however,the effects of these mt-tRNA variants on T2DM progression are largely unknown.AIM To assess the potential pathogenicity of T2DM-associated m.A5514G and m.C12237T variants at genetic,molecular,and biochemical levels.METHODS Cytoplasmic hybrid(cybrid)cells carrying both m.A5514G and m.C12237T variants,and healthy control cells without these mitochondrial DNA(mtDNA)variants were generated using trans-mitochondrial technology.Mitochondrial features,including mt-tRNA steady-state level,levels of adenosine triphosphate(ATP),mitochondrial membrane potential(MMP),reactive oxygen species(ROS),mtDNA copy number,nicotinamide adenine dinucleotide(NAD+)/NADH ratio,enzymatic activities of respiratory chain complexes(RCCs),8-hydroxy-deoxyguanine(8-OhdG),malondialdehyde(MDA),and superoxide dismutase(SOD)were examined in cell lines with and without these mt-tRNA variants.RESULTS Compared with control cells,the m.A5514G variant caused an approximately 35%reduction in the steady-state level of mt-tRNA^(Trp)(P<0.0001);however,the m.C12237T variant did not affect the mt-tRNA^(Ser(AGY))steady-state level(P=0.5849).Biochemical analysis revealed that cells with both m.A5514G and m.C12237T variants exhibited more severe mitochondrial dysfunctions and elevated oxidative stress than control cells:ATP,MMP,NAD+/NADH ratio,enzyme activities of RCCs and SOD levels were markedly decreased in mutant cells(P<0.05 for all measures).By contrast,the levels of ROS,8-OhdG and MDA were significantly increased(P<0.05 for all measures),but mtDNA copy number was not affected by m.A5514G and m.C12237T variants(P=0.5942).CONCLUSION The m.A5514G variant impaired mt-tRNA^(Trp)metabolism,which subsequently caused mitochondrial dysfunction.The m.C12237T variant did not alter the steady-state level of mt-tRNA^(Ser(AGY)),indicating that it may be a modifier of the m.A5514G variant.The m.A5514G variant may exacerbate the pathogenesis and progression of T2DM in this Chinese pedigree.
文摘目的:探讨新型冠状病毒奥米克戎株(Omicron Variant of Sars-Cov-2)对心脏外科围术期的相关影响。方法:选取自2022年12月12日至2023年1月19日期间,安贞医院心外科行心脏外科手术患者104例,收集患者一般临床资料、围手术期相关情况,根据病原学转阴至手术日之间的天数,并根据天数分组,对新型冠状相关并发症进行回顾性研究,并对其相关性进行探讨。结果:本研究中共出现3例死亡患者,死亡原因2例是核酸复阳导致新型冠状病毒肺炎引发的低氧血症,1例是循环衰竭伴弥散性血管内凝血;转阴<1周组在在呼吸机使用时间及ICU停留时间方面显著长于其他各组;早期手术组呼吸机使用时间、ICU停留时间、二次气管插管及出现新型冠状病毒肺炎等方面均显著高于晚期手术组。结论:新型冠状奥米克戎株“阳康”早期内行心脏手术可能会影响预后;尤其是病原学转阴<14d患者在呼吸机使用时间、ICU停留时间、二次气管插管及出现新型冠状病毒肺炎等方面风险显著增加。
