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

Katharina Danhauser; Bader Alhaddad; Christine Makowski; Dorota Piekutowska-Abramczuk; Steffen Syrbe; Natalia Gomez-Ospina; Melanie A. Manning; Anna Kostera-Pruszczyk; Claudia Krahn-Peper; Riccardo Berutti; Reka Kovács-Nagy; Mirjana Gusic; Elisabeth Graf; Lucia Laugwitz; Michaela Röblitz; Andreas Wroblewski; Hans Hartmann; Anibh M. Das; Eva Bültmann; Fang Fang; Manting Xu; Ulrich A. Schatz; Daniela Karall; Herta Zellner; Edda Haberlandt; René G. Feichtinger; Johannes A. Mayr; Thomas Meitinger; Holger Prokisch; Tim M. Strom; Rafał Płoski; Georg F. Hoffmann; Maciej Pronicki; Penelope E. Bonnen; Susanne Morlot; Tobias B. Haack

doi:10.1016/j.ajhg.2018.10.005

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

Katharina Danhauser, Bader Alhaddad, Christine Makowski, Dorota Piekutowska-Abramczuk, Steffen Syrbe, Natalia Gomez-Ospina, Melanie A. Manning, Anna Kostera-Pruszczyk, Claudia Krahn-Peper, Riccardo Berutti, Reka Kovács-Nagy, Mirjana Gusic, Elisabeth Graf, Lucia Laugwitz, Michaela Röblitz, Andreas Wroblewski, Hans Hartmann, Anibh M. Das, Eva Bültmann, Fang FangManting Xu, Ulrich A. Schatz, Daniela Karall, Herta Zellner, Edda Haberlandt, René G. Feichtinger, Johannes A. Mayr, Thomas Meitinger, Holger Prokisch, Tim M. Strom, Rafał Płoski, Georg F. Hoffmann, Maciej Pronicki, Penelope E. Bonnen, Susanne Morlot, Tobias B. Haack

Medicine and Health

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44 Scopus citations

Abstract

ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose 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.

Original language	English
Pages (from-to)	817-825
Number of pages	9
Journal	American Journal of Human Genetics
Volume	103
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2018.10.005
State	Published - 1 Nov 2018

Keywords

ADPRHL2
ARH3
PARP
ataxia
cerebellar atrophy
neurodegeneration
neuropathy
posttranslational modification
ribosylation
seizure

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10.1016/j.ajhg.2018.10.005

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Danhauser, K., Alhaddad, B., Makowski, C., Piekutowska-Abramczuk, D., Syrbe, S., Gomez-Ospina, N., Manning, M. A., Kostera-Pruszczyk, A., Krahn-Peper, C., Berutti, R., Kovács-Nagy, R., Gusic, M., Graf, E., Laugwitz, L., Röblitz, M., Wroblewski, A., Hartmann, H., Das, A. M., Bültmann, E., ... Haack, T. B. (2018). Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy. American Journal of Human Genetics, 103(5), 817-825. https://doi.org/10.1016/j.ajhg.2018.10.005

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

abstract = "ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose 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{\textquoteright} 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.",

keywords = "ADPRHL2, ARH3, PARP, ataxia, cerebellar atrophy, neurodegeneration, neuropathy, posttranslational modification, ribosylation, seizure",

author = "Katharina Danhauser and Bader Alhaddad and Christine Makowski and Dorota Piekutowska-Abramczuk and Steffen Syrbe and Natalia Gomez-Ospina and Manning, {Melanie A.} and Anna Kostera-Pruszczyk and Claudia Krahn-Peper and Riccardo Berutti and Reka Kov{\'a}cs-Nagy and Mirjana Gusic and Elisabeth Graf and Lucia Laugwitz and Michaela R{\"o}blitz and Andreas Wroblewski and Hans Hartmann and Das, {Anibh M.} and Eva B{\"u}ltmann and Fang Fang and Manting Xu and Schatz, {Ulrich A.} and Daniela Karall and Herta Zellner and Edda Haberlandt and Feichtinger, {Ren{\'e} G.} and Mayr, {Johannes A.} and Thomas Meitinger and Holger Prokisch and Strom, {Tim M.} and Rafa{\l} P{\l}oski and Hoffmann, {Georg F.} and Maciej Pronicki and Bonnen, {Penelope E.} and Susanne Morlot and Haack, {Tobias B.}",

note = "Publisher Copyright: {\textcopyright} 2018 American Society of Human Genetics",

year = "2018",

month = nov,

day = "1",

doi = "10.1016/j.ajhg.2018.10.005",

language = "English",

volume = "103",

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journal = "American Journal of Human Genetics",

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Danhauser, K, Alhaddad, B, Makowski, C, Piekutowska-Abramczuk, D, Syrbe, S, Gomez-Ospina, N, Manning, MA, Kostera-Pruszczyk, A, Krahn-Peper, C, Berutti, R, Kovács-Nagy, R, Gusic, M, Graf, E, Laugwitz, L, Röblitz, M, Wroblewski, A, Hartmann, H, Das, AM, Bültmann, E, Fang, F, Xu, M, Schatz, UA, Karall, D, Zellner, H, Haberlandt, E, Feichtinger, RG, Mayr, JA, Meitinger, T, Prokisch, H, Strom, TM, Płoski, R, Hoffmann, GF, Pronicki, M, Bonnen, PE, Morlot, S & Haack, TB 2018, 'Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy', American Journal of Human Genetics, vol. 103, no. 5, pp. 817-825. https://doi.org/10.1016/j.ajhg.2018.10.005

TY - JOUR

T1 - Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy

AU - Danhauser, Katharina

AU - Alhaddad, Bader

AU - Makowski, Christine

AU - Piekutowska-Abramczuk, Dorota

AU - Syrbe, Steffen

AU - Gomez-Ospina, Natalia

AU - Manning, Melanie A.

AU - Kostera-Pruszczyk, Anna

AU - Krahn-Peper, Claudia

AU - Berutti, Riccardo

AU - Kovács-Nagy, Reka

AU - Gusic, Mirjana

AU - Graf, Elisabeth

AU - Laugwitz, Lucia

AU - Röblitz, Michaela

AU - Wroblewski, Andreas

AU - Hartmann, Hans

AU - Das, Anibh M.

AU - Bültmann, Eva

AU - Fang, Fang

AU - Xu, Manting

AU - Schatz, Ulrich A.

AU - Karall, Daniela

AU - Zellner, Herta

AU - Haberlandt, Edda

AU - Feichtinger, René G.

AU - Mayr, Johannes A.

AU - Meitinger, Thomas

AU - Prokisch, Holger

AU - Strom, Tim M.

AU - Płoski, Rafał

AU - Hoffmann, Georg F.

AU - Pronicki, Maciej

AU - Bonnen, Penelope E.

AU - Morlot, Susanne

AU - Haack, Tobias B.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose 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.

AB - ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose 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.

KW - ADPRHL2

KW - ARH3

KW - PARP

KW - ataxia

KW - cerebellar atrophy

KW - neurodegeneration

KW - neuropathy

KW - posttranslational modification

KW - ribosylation

KW - seizure

UR - http://www.scopus.com/inward/record.url?scp=85055102775&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.10.005

DO - 10.1016/j.ajhg.2018.10.005

M3 - Article

C2 - 30401461

AN - SCOPUS:85055102775

SN - 0002-9297

VL - 103

SP - 817

EP - 825

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

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

Abstract

Keywords

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