Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy

Arcangela Iuso, Marit Wiersma, Hans Joachim Schüller, Ben Pode-Shakked, Dina Marek-Yagel, Mathias Grigat, Thomas Schwarzmayr, Riccardo Berutti, Bader Alhaddad, Bart Kanon, Nicola A. Grzeschik, Jürgen G. Okun, Zeev Perles, Yishay Salem, Ortal Barel, Amir Vardi, Marina Rubinshtein, Tal Tirosh, Gal Dubnov-Raz, Ana C. Messias & 18 others Caterina Terrile, Iris Barshack, Alex Volkov, Camilla Avivi, Eran Eyal, Elisa Mastantuono, Muhamad Kumbar, Shachar Abudi, Matthias Braunisch, Tim M. Strom, Thomas Meitinger, Georg F. Hoffmann, Holger Prokisch, Tobias B. Haack, Bianca J.J.M. Brundel, Dorothea Haas, Ody C.M. Sibon, Yair Anikster

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

Original languageEnglish
Pages (from-to)1018-1030
Number of pages13
JournalAmerican journal of human genetics
Volume102
Issue number6
DOIs
Publication statusPublished - 7 Jun 2018

Cite this

Iuso, A., Wiersma, M., Schüller, H. J., Pode-Shakked, B., Marek-Yagel, D., Grigat, M., ... Anikster, Y. (2018). Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy. American journal of human genetics, 102(6), 1018-1030. https://doi.org/10.1016/j.ajhg.2018.03.022
Iuso, Arcangela ; Wiersma, Marit ; Schüller, Hans Joachim ; Pode-Shakked, Ben ; Marek-Yagel, Dina ; Grigat, Mathias ; Schwarzmayr, Thomas ; Berutti, Riccardo ; Alhaddad, Bader ; Kanon, Bart ; Grzeschik, Nicola A. ; Okun, Jürgen G. ; Perles, Zeev ; Salem, Yishay ; Barel, Ortal ; Vardi, Amir ; Rubinshtein, Marina ; Tirosh, Tal ; Dubnov-Raz, Gal ; Messias, Ana C. ; Terrile, Caterina ; Barshack, Iris ; Volkov, Alex ; Avivi, Camilla ; Eyal, Eran ; Mastantuono, Elisa ; Kumbar, Muhamad ; Abudi, Shachar ; Braunisch, Matthias ; Strom, Tim M. ; Meitinger, Thomas ; Hoffmann, Georg F. ; Prokisch, Holger ; Haack, Tobias B. ; Brundel, Bianca J.J.M. ; Haas, Dorothea ; Sibon, Ody C.M. ; Anikster, Yair. / Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy. In: American journal of human genetics. 2018 ; Vol. 102, No. 6. pp. 1018-1030.
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abstract = "Coenzyme A (CoA) is an essential metabolic cofactor used by around 4{\%} of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.",
keywords = "coenzyme A, dilated cardiomyopathy, pantethine treatment, pentothenate, phospohopantothenoylcysteine synthetase, PPCS",
author = "Arcangela Iuso and Marit Wiersma and Sch{\"u}ller, {Hans Joachim} and Ben Pode-Shakked and Dina Marek-Yagel and Mathias Grigat and Thomas Schwarzmayr and Riccardo Berutti and Bader Alhaddad and Bart Kanon and Grzeschik, {Nicola A.} and Okun, {J{\"u}rgen G.} and Zeev Perles and Yishay Salem and Ortal Barel and Amir Vardi and Marina Rubinshtein and Tal Tirosh and Gal Dubnov-Raz and Messias, {Ana C.} and Caterina Terrile and Iris Barshack and Alex Volkov and Camilla Avivi and Eran Eyal and Elisa Mastantuono and Muhamad Kumbar and Shachar Abudi and Matthias Braunisch and Strom, {Tim M.} and Thomas Meitinger and Hoffmann, {Georg F.} and Holger Prokisch and Haack, {Tobias B.} and Brundel, {Bianca J.J.M.} and Dorothea Haas and Sibon, {Ody C.M.} and Yair Anikster",
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Iuso, A, Wiersma, M, Schüller, HJ, Pode-Shakked, B, Marek-Yagel, D, Grigat, M, Schwarzmayr, T, Berutti, R, Alhaddad, B, Kanon, B, Grzeschik, NA, Okun, JG, Perles, Z, Salem, Y, Barel, O, Vardi, A, Rubinshtein, M, Tirosh, T, Dubnov-Raz, G, Messias, AC, Terrile, C, Barshack, I, Volkov, A, Avivi, C, Eyal, E, Mastantuono, E, Kumbar, M, Abudi, S, Braunisch, M, Strom, TM, Meitinger, T, Hoffmann, GF, Prokisch, H, Haack, TB, Brundel, BJJM, Haas, D, Sibon, OCM & Anikster, Y 2018, 'Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy' American journal of human genetics, vol. 102, no. 6, pp. 1018-1030. https://doi.org/10.1016/j.ajhg.2018.03.022

Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy. / Iuso, Arcangela; Wiersma, Marit; Schüller, Hans Joachim; Pode-Shakked, Ben; Marek-Yagel, Dina; Grigat, Mathias; Schwarzmayr, Thomas; Berutti, Riccardo; Alhaddad, Bader; Kanon, Bart; Grzeschik, Nicola A.; Okun, Jürgen G.; Perles, Zeev; Salem, Yishay; Barel, Ortal; Vardi, Amir; Rubinshtein, Marina; Tirosh, Tal; Dubnov-Raz, Gal; Messias, Ana C.; Terrile, Caterina; Barshack, Iris; Volkov, Alex; Avivi, Camilla; Eyal, Eran; Mastantuono, Elisa; Kumbar, Muhamad; Abudi, Shachar; Braunisch, Matthias; Strom, Tim M.; Meitinger, Thomas; Hoffmann, Georg F.; Prokisch, Holger; Haack, Tobias B.; Brundel, Bianca J.J.M.; Haas, Dorothea; Sibon, Ody C.M.; Anikster, Yair.

In: American journal of human genetics, Vol. 102, No. 6, 07.06.2018, p. 1018-1030.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy

AU - Iuso, Arcangela

AU - Wiersma, Marit

AU - Schüller, Hans Joachim

AU - Pode-Shakked, Ben

AU - Marek-Yagel, Dina

AU - Grigat, Mathias

AU - Schwarzmayr, Thomas

AU - Berutti, Riccardo

AU - Alhaddad, Bader

AU - Kanon, Bart

AU - Grzeschik, Nicola A.

AU - Okun, Jürgen G.

AU - Perles, Zeev

AU - Salem, Yishay

AU - Barel, Ortal

AU - Vardi, Amir

AU - Rubinshtein, Marina

AU - Tirosh, Tal

AU - Dubnov-Raz, Gal

AU - Messias, Ana C.

AU - Terrile, Caterina

AU - Barshack, Iris

AU - Volkov, Alex

AU - Avivi, Camilla

AU - Eyal, Eran

AU - Mastantuono, Elisa

AU - Kumbar, Muhamad

AU - Abudi, Shachar

AU - Braunisch, Matthias

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Hoffmann, Georg F.

AU - Prokisch, Holger

AU - Haack, Tobias B.

AU - Brundel, Bianca J.J.M.

AU - Haas, Dorothea

AU - Sibon, Ody C.M.

AU - Anikster, Yair

PY - 2018/6/7

Y1 - 2018/6/7

N2 - Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

AB - Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.

KW - coenzyme A

KW - dilated cardiomyopathy

KW - pantethine treatment

KW - pentothenate

KW - phospohopantothenoylcysteine synthetase

KW - PPCS

UR - http://www.scopus.com/inward/record.url?scp=85046776501&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.03.022

DO - 10.1016/j.ajhg.2018.03.022

M3 - Article

VL - 102

SP - 1018

EP - 1030

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

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ER -