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首页> 外文期刊>Clinical Genetics: An International Journal of Genetics in Medicine >Mitochondrial epileptic encephalopathy, 3‐methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 TIMM50 TIMM50 mutations
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Mitochondrial epileptic encephalopathy, 3‐methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 TIMM50 TIMM50 mutations

机译：线粒体癫痫患者，3-甲基戊酸尿尿和可变复合V缺乏与TIMM50 TIMM50 TIMM50突变相关

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摘要

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser , in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3‐methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3‐methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met , in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3‐methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3‐methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.
机译：线粒体脑病是一种异质疾病，通常携带严重预后。最近，在TimM50基因中，纯合的突变，GLY372SER以抽象形式报告，其中三种SIBS患者患有顽固的癫痫和发育延迟伴有3-甲基戊烯酸尿症。我们现在报告了来自患有严重智力残疾和癫痫发作的两名无关家庭的四名患者，伴随着乳酸鲜乳酸水平略微升高，3-甲基戊脲和线粒体复合体的可变缺乏。使用Exome分析我们确定了两个纯合物畸变突变，arg217TRP和thr252met，在timm50基因中。 TIMM50蛋白是TIM23复合物的亚基，线粒体进口机械。它用作膜间隙中的主要受体，与蛋白质结合，蛋白质在其前往基质的途中交叉。影响进化保守的残留物并与家庭中的疾病进行隔离的突变既不存在于大型控制exome分析的大型队列，也不存在于我们的种族特定的外壳队列。鉴于表型相似性，我们得出结论，TIMM50中的畸形突变可能伴随着3-甲基戊糖尿的严重智力残疾和癫痫症和可变线粒体复合V缺乏症。作为线粒体功能障碍的重要生物标志物，3-甲基戊康酸尿是一种重要的生物标志物，特别是用于线粒体膜缺陷。

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    Shahrour M.A.; Staretz‐Chacham O.; Dayan D.; Stephen J.; Weech A.; Damseh N.; Pri Chen H.; Edvardson S.; Mazaheri S.; Saada A.; NISC Intramural Sequencing; Hershkovitz E.; Shaag A.; Huizing M.; Abu‐Libdeh B.; Gahl W.A; Azem A.; Anikster Y.; Vilboux T.; Elpeleg O.; Malicdan M.C.;

  • 作者单位

    Department of PediatricsAl‐Makassed Islamic HospitalJerusalem Israel;

    Metabolic Disease UnitSoroka Medical Center Faculty of Health Sciences Ben‐Gurion University of;

    Department of Biochemistry &

    Molecular BiologyTel Aviv UniversityTel Aviv Israel;

    Section of Human Biochemical Genetics Medical Genetics BranchNational Human Genome Research;

    NIH Undiagnosed Diseases ProgramNational Human Genome Research Institute National Institutes of;

    Department of PediatricsAl‐Makassed Islamic HospitalJerusalem Israel;

    Department of Biochemistry &

    Molecular BiologyTel Aviv UniversityTel Aviv Israel;

    Pediatric Neurology UnitHadassah Hebrew University Medical Center JerusalemJerusalem Israel;

    Section of Human Biochemical Genetics Medical Genetics BranchNational Human Genome Research;

    Monique and Jacques Roboh Department of Genetic ResearchHadassah Hebrew University Medical Center;

    NIH Intramural Sequencing Center (NISC)National Human Genome Research Institute National;

    Metabolic Disease UnitSoroka Medical Center Faculty of Health Sciences Ben‐Gurion University of;

    NIH Intramural Sequencing Center (NISC)National Human Genome Research Institute National;

    Section of Human Biochemical Genetics Medical Genetics BranchNational Human Genome Research;

    Department of PediatricsAl‐Makassed Islamic HospitalJerusalem Israel;

    Section of Human Biochemical Genetics Medical Genetics BranchNational Human Genome Research;

    Department of Biochemistry &

    Molecular BiologyTel Aviv UniversityTel Aviv Israel;

    Metabolic Disease UnitEdmond and Lily Safra Children's Hospital Sheba Medical CenterTel‐Hashomer;

    NIH Undiagnosed Diseases ProgramNational Human Genome Research Institute National Institutes of;

    NIH Intramural Sequencing Center (NISC)National Human Genome Research Institute National;

    Section of Human Biochemical Genetics Medical Genetics BranchNational Human Genome Research;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学遗传学;
  • 关键词

    3‐methylglutaconic aciduria; epileptic encephalopathy; exome analysis; mitochondria; TIMM50;

    机译：3-甲基戊康氏尿;癫痫脑病;exome分析;线粒体;TIMM50;

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