Variants in ATP5F1B are associated with dominantly inherited dystonia

Alessia Nasca; Niccolò E. Mencacci; Federica Invernizzi; Michael Zech; Ignacio J. Keller Sarmiento; Andrea Legati; Chiara Frascarelli; Bernabe I. Bustos; Luigi M. Romito; Dimitri Krainc; Juliane Winkelmann; Miryam Carecchio; Nardo Nardocci; Giovanna Zorzi; Holger Prokisch; Steven J. Lubbe; Barbara Garavaglia; Daniele Ghezzi

doi:10.1093/brain/awad068

Variants in ATP5F1B are associated with dominantly inherited dystonia

Alessia Nasca, Niccolò E. Mencacci, Federica Invernizzi, Michael Zech, Ignacio J. Keller Sarmiento, Andrea Legati, Chiara Frascarelli, Bernabe I. Bustos, Luigi M. Romito, Dimitri Krainc, Juliane Winkelmann, Miryam Carecchio, Nardo Nardocci, Giovanna Zorzi, Holger Prokisch, Steven J. Lubbe, Barbara Garavaglia, Daniele Ghezzi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.

Original language	English (US)
Pages (from-to)	2730-2738
Number of pages	9
Journal	Brain
Volume	146
Issue number	7
DOIs	https://doi.org/10.1093/brain/awad068
State	Published - Jul 1 2023

Funding

This research was funded by the ERA PerMed project PerMiM (Italian Ministry of Health ERP-2019-23671048 and the German Federal Ministry of Education and Research 01KU2016A), the European Joint Programme on Rare Diseases (EJP RD) project GENOMIT (Italian Ministry of Health ERP-2019-23671045 and German Federal Ministry of Education and Research 01GM1920A), the Mariani Foundation (CM23), the Italian Ministry of Health (RRC to D.G.), Parkinson’s Foundation (to N.E.M.). M.Z. and J.W. receive research support from the German Research Foundation (DFG 458949627; ZE 1213/2-1; WI 1820/14-1).

Keywords

ATP5F1B
case report
dystonia
incomplete penetrance
mitochondrial ATP synthase

ASJC Scopus subject areas

Clinical Neurology

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10.1093/brain/awad068

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Nasca, A., Mencacci, N. E., Invernizzi, F., Zech, M., Keller Sarmiento, I. J., Legati, A., Frascarelli, C., Bustos, B. I., Romito, L. M., Krainc, D., Winkelmann, J., Carecchio, M., Nardocci, N., Zorzi, G., Prokisch, H., Lubbe, S. J., Garavaglia, B., & Ghezzi, D. (2023). Variants in ATP5F1B are associated with dominantly inherited dystonia. Brain, 146(7), 2730-2738. https://doi.org/10.1093/brain/awad068

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title = "Variants in ATP5F1B are associated with dominantly inherited dystonia",

abstract = "ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.",

keywords = "ATP5F1B, case report, dystonia, incomplete penetrance, mitochondrial ATP synthase",

author = "Alessia Nasca and Mencacci, {Niccol{\`o} E.} and Federica Invernizzi and Michael Zech and {Keller Sarmiento}, {Ignacio J.} and Andrea Legati and Chiara Frascarelli and Bustos, {Bernabe I.} and Romito, {Luigi M.} and Dimitri Krainc and Juliane Winkelmann and Miryam Carecchio and Nardo Nardocci and Giovanna Zorzi and Holger Prokisch and Lubbe, {Steven J.} and Barbara Garavaglia and Daniele Ghezzi",

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year = "2023",

month = jul,

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doi = "10.1093/brain/awad068",

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Nasca, A, Mencacci, NE, Invernizzi, F, Zech, M, Keller Sarmiento, IJ, Legati, A, Frascarelli, C, Bustos, BI, Romito, LM, Krainc, D, Winkelmann, J, Carecchio, M, Nardocci, N, Zorzi, G, Prokisch, H, Lubbe, SJ, Garavaglia, B & Ghezzi, D 2023, 'Variants in ATP5F1B are associated with dominantly inherited dystonia', Brain, vol. 146, no. 7, pp. 2730-2738. https://doi.org/10.1093/brain/awad068

TY - JOUR

T1 - Variants in ATP5F1B are associated with dominantly inherited dystonia

AU - Nasca, Alessia

AU - Mencacci, Niccolò E.

AU - Invernizzi, Federica

AU - Zech, Michael

AU - Keller Sarmiento, Ignacio J.

AU - Legati, Andrea

AU - Frascarelli, Chiara

AU - Bustos, Bernabe I.

AU - Romito, Luigi M.

AU - Krainc, Dimitri

AU - Winkelmann, Juliane

AU - Carecchio, Miryam

AU - Nardocci, Nardo

AU - Zorzi, Giovanna

AU - Prokisch, Holger

AU - Lubbe, Steven J.

AU - Garavaglia, Barbara

AU - Ghezzi, Daniele

PY - 2023/7/1

Y1 - 2023/7/1

N2 - ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.

AB - ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. Pathogenic variants in nuclear genes encoding assembly factors or structural subunits are associated with complex V deficiency, typically characterized by autosomal recessive inheritance and multisystem phenotypes. Movement disorders have been described in a subset of cases carrying autosomal dominant variants in structural subunits genes ATP5F1A and ATP5MC3. Here, we report the identification of two different ATP5F1B missense variants (c.1000A>C; p.Thr334Pro and c.1445T>C; p.Val482Ala) segregating with early-onset isolated dystonia in two families, both with autosomal dominant mode of inheritance and incomplete penetrance. Functional studies in mutant fibroblasts revealed no decrease of ATP5F1B protein amount but severe reduction of complex V activity and impaired mitochondrial membrane potential, suggesting a dominant-negative effect. In conclusion, our study describes a new candidate gene associated with isolated dystonia and confirms that heterozygous variants in genes encoding subunits of the mitochondrial ATP synthase may cause autosomal dominant isolated dystonia with incomplete penetrance, likely through a dominant-negative mechanism.

KW - ATP5F1B

KW - case report

KW - dystonia

KW - incomplete penetrance

KW - mitochondrial ATP synthase

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U2 - 10.1093/brain/awad068

DO - 10.1093/brain/awad068

M3 - Article

C2 - 36860166

AN - SCOPUS:85164235279

SN - 0006-8950

VL - 146

SP - 2730

EP - 2738

JO - Brain

JF - Brain

IS - 7

ER -

Variants in ATP5F1B are associated with dominantly inherited dystonia

Abstract

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