机构：[1]Institute of Human Genetics, Technische Universita¨t Mu¨nchen, 81675 Munich, Germany[2]Institute of Human Genetics, Helmholtz Zentrum Mu¨nchen, 85764 Neuherberg, Germany[3]Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig Maximilian University of Munich, 80337Munich, Germany[4]Department of Pediatrics, Technische Universita¨t Mu¨nchen, 80804 Munich, Germany[5]Department of Medical Genetics, Children’s Memorial Health Institute, 04-730Warsaw, Poland[6]Division of Neuropediatrics and Metabolic Medicine, University Children’s Hospital, 69120 Heidelberg, Germany[7]Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA[8]Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA[9]Department of Neurology, Medical University of Warsaw, 02-097 Warsaw, Poland[10]Sozialpa¨diatrisches Zentrum, Heilpa¨dagogisch Therapeutisches Zentrum gGmbH, 56564 Neuwied, Germany[11]Division of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, 72072 Tu¨bingen, Germany[12]Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tu¨bingen, Germany[13]St. Joseph Krankenhaus, Zentrum Kinder- und Jugendmedizin,Wu¨sthoffstr. 15, 12101 Berlin, Germany[14]Clinic for Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany[15]Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, 30625 Hannover, Germany[16]Department of Pediatric Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, 100045 Beijing, China临床科室职能科室临床流行病与循证医学中心泌尿外科首都医科大学附属北京儿童医院[17]Division of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria[18]Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria[19]Clinic for Pediatrics, Krankenhaus Stadt Dornbirn, 6850 Dornbirn, Austria[20]Department of Pediatrics, ParacelsusMedical University Salzburg, 5020 Salzburg, Austria[21]Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, German[22]Department of Medical Genetics, Medical University ofWarsaw, 02-106 Warsaw, Poland[23]Department of Pathology, Children’s Memorial Health Institute, 04-730 Warsaw, Poland[24]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA[25]Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany[26]Centre for Rare Diseases, University of Tuebingen, 72076 Tu¨bingen, Germany
ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADPribose from NAD(+) to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-) motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.
基金：
German Bundesministerium fur Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin "mitOmics''Federal Ministry of Education & Research (BMBF) [FKZ 01ZX1405C]; E-Rare project GENOMIT [01GM1603, 01GM1207]; EU FP7 Mitochondrial European Educational Training Project [317433]; EU Horizon2020 Collaborative Research Project SOUND [633974]; National Science Centre (NCN) Poland [2013/11/B/NZ7/04944]; National Institute of Neurological Disorders and Stroke of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [R01NS08372]; Key Special Project of National Key Research and Development Program "Research on prevention and control of major chronic non-communicable diseases: Early identification and comprehensive intervention of brain development disorders in children''; [S148/16]; [S145/16]
第一作者机构：[1]Institute of Human Genetics, Technische Universita¨t Mu¨nchen, 81675 Munich, Germany[2]Institute of Human Genetics, Helmholtz Zentrum Mu¨nchen, 85764 Neuherberg, Germany[3]Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, Ludwig Maximilian University of Munich, 80337Munich, Germany
通讯作者：
通讯机构：[1]Institute of Human Genetics, Technische Universita¨t Mu¨nchen, 81675 Munich, Germany[12]Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tu¨bingen, Germany[26]Centre for Rare Diseases, University of Tuebingen, 72076 Tu¨bingen, Germany
推荐引用方式(GB/T 7714)：
Danhauser Katharina,Alhaddad Bader,Makowski Christine,et al.Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy[J].AMERICAN JOURNAL OF HUMAN GENETICS.2018,103(5):817-825.doi:10.1016/j.ajhg.2018.10.005.
APA：
Danhauser, Katharina,Alhaddad, Bader,Makowski, Christine,Piekutowska-Abramczuk, Dorota,Syrbe, Steffen...&Haack, Tobias B..(2018).Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy.AMERICAN JOURNAL OF HUMAN GENETICS,103,(5)
MLA：
Danhauser, Katharina,et al."Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy".AMERICAN JOURNAL OF HUMAN GENETICS 103..5(2018):817-825
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