Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy

被引:43
|
作者
Danhauser, Katharina [1 ,2 ,3 ]
Alhaddad, Bader [1 ,2 ]
Makowski, Christine [4 ]
Piekutowska-Abramczuk, Dorota [5 ]
Syrbe, Steffen [6 ]
Gomez-Ospina, Natalia [7 ,8 ]
Manning, Melanie A. [7 ,8 ]
Kostera-Pruszczyk, Anna [9 ]
Krahn-Peper, Claudia [10 ]
Berutti, Riccardo [2 ]
Kovacs-Nagy, Reka [1 ]
Gusic, Mirjana [1 ,2 ]
Graf, Elisabeth [2 ]
Laugwitz, Lucia [11 ,12 ]
Roeblitz, Michaela [13 ]
Wroblewski, Andreas [13 ]
Hartmann, Hans [14 ]
Das, Anibh M. [14 ]
Bueltmann, Eva [15 ]
Fang, Fang [16 ]
Xu, Manting [16 ]
Schatz, Ulrich A. [1 ,17 ]
Karall, Daniela [18 ]
Zellner, Herta [18 ]
Haberlandt, Edda [19 ]
Feichtinger, Rene G. [20 ]
Mayr, Johannes A. [20 ]
Meitinger, Thomas [1 ,2 ,21 ]
Prokisch, Holger [1 ,2 ,16 ]
Strom, Tim M. [1 ,2 ]
Ploski, Rafal [22 ]
Hoffmann, Georg F. [6 ]
Pronicki, Maciej [23 ]
Bonnen, Penelope E. [24 ]
Morlot, Susanne [25 ]
Haack, Tobias B. [1 ,12 ,26 ]
机构
[1] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany
[2] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany
[3] Ludwig Maximilian Univ Munich, Univ Hosp, Dr von Hauner Childrens Hosp, Dept Pediat, D-80337 Munich, Germany
[4] Tech Univ Munich, Dept Pediat, D-80804 Munich, Germany
[5] Childrens Mem Hlth Inst, Dept Med Genet, PL-04730 Warsaw, Poland
[6] Univ Childrens Hosp, Div Neuropediat & Metab Med, D-69120 Heidelberg, Germany
[7] Stanford Univ, Sch Med, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA
[8] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA
[9] Med Univ Warsaw, Dept Neurol, PL-02097 Warsaw, Poland
[10] Heilpadag Therapeut Zentrum gGmbH, Sozialpadiatr Zentrum, Neuwied D-56564, Greece
[11] Univ Childrens Hosp, Div Pediat Neurol & Dev Med, D-72072 Tubingen, Germany
[12] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany
[13] St Josephs Hosp, Zentrum Kinder & Jugendmed, Wusthoffstr 15, D-12101 Berlin, Germany
[14] Hannover Med Sch, Clin Pediat Kidney Liver & Metab Dis, D-30625 Hannover, Germany
[15] Hannover Med Sch, Inst Diagnost & Intervent Neuroradiol, D-30625 Hannover, Germany
[16] Capital Med Univ, Beijing Childrens Hosp, Dept Pediat Neurol, Natl Ctr Childrens Hlth, Beijing 100045, Peoples R China
[17] Med Univ Innsbruck, Div Human Genet, A-6020 Innsbruck, Austria
[18] Med Univ Innsbruck, Pediat Clin, Div Inherited Metab Disorders, A-6020 Innsbruck, Austria
[19] Krankenhaus Stadt Dornbirn, Pediat Clin, A-6850 Dornbirn, Austria
[20] ParacelsusMed Univ Salzburg, Dept Pediat, A-5020 Salzburg, Austria
[21] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany
[22] Med Univ Warsaw, Dept Med Genet, PL-02106 Warsaw, Poland
[23] Childrens Mem Hlth Inst, Dept Pathol, PL-04730 Warsaw, Poland
[24] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[25] Hannover Med Sch, Inst Human Genet, D-30625 Hannover, Germany
[26] Univ Tubingen, Ctr Rare Dis, D-72076 Tubingen, Germany
基金
美国国家卫生研究院;
关键词
POLY ADP-RIBOSE; CELL-DEATH; POLY(ADP-RIBOSE); DEGRADATION; ENZYMES;
D O I
10.1016/j.ajhg.2018.10.005
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:817 / 825
页数:9
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