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Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase

BACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in t...

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Autores principales: Soreze, Yohan, Boutron, Audrey, Habarou, Florence, Barnerias, Christine, Nonnenmacher, Luc, Delpech, Hélène, Mamoune, Asmaa, Chrétien, Dominique, Hubert, Laurence, Bole-Feysot, Christine, Nitschke, Patrick, Correia, Isabelle, Sardet, Claude, Boddaert, Nathalie, Hamel, Yamina, Delahodde, Agnès, Ottolenghi, Chris, de Lonlay, Pascale
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905285/
https://www.ncbi.nlm.nih.gov/pubmed/24341803
http://dx.doi.org/10.1186/1750-1172-8-192
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author Soreze, Yohan
Boutron, Audrey
Habarou, Florence
Barnerias, Christine
Nonnenmacher, Luc
Delpech, Hélène
Mamoune, Asmaa
Chrétien, Dominique
Hubert, Laurence
Bole-Feysot, Christine
Nitschke, Patrick
Correia, Isabelle
Sardet, Claude
Boddaert, Nathalie
Hamel, Yamina
Delahodde, Agnès
Ottolenghi, Chris
de Lonlay, Pascale
author_facet Soreze, Yohan
Boutron, Audrey
Habarou, Florence
Barnerias, Christine
Nonnenmacher, Luc
Delpech, Hélène
Mamoune, Asmaa
Chrétien, Dominique
Hubert, Laurence
Bole-Feysot, Christine
Nitschke, Patrick
Correia, Isabelle
Sardet, Claude
Boddaert, Nathalie
Hamel, Yamina
Delahodde, Agnès
Ottolenghi, Chris
de Lonlay, Pascale
author_sort Soreze, Yohan
collection PubMed
description BACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (α-KGDHc) and branched chain α-keto acid dehydrogenase (BCKDHc) complexes. METHODS: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts. RESULTS: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and α-KGDH E2 subunits. Accordingly, the production of (14)CO(2) by patient fibroblasts after incubation with (14C)glucose, (14C)butyrate or (14C)3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and α-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants. CONCLUSION: We report here a putative case of impaired free or H protein-derived lipoic acid attachment due to LIPT1 mutations as a cause of PDH and α-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies.
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spelling pubmed-39052852014-01-30 Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase Soreze, Yohan Boutron, Audrey Habarou, Florence Barnerias, Christine Nonnenmacher, Luc Delpech, Hélène Mamoune, Asmaa Chrétien, Dominique Hubert, Laurence Bole-Feysot, Christine Nitschke, Patrick Correia, Isabelle Sardet, Claude Boddaert, Nathalie Hamel, Yamina Delahodde, Agnès Ottolenghi, Chris de Lonlay, Pascale Orphanet J Rare Dis Research BACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described (i.e., LIAS, NFU1, BOLA3, IBA57), but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (α-KGDHc) and branched chain α-keto acid dehydrogenase (BCKDHc) complexes. METHODS: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and α-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts. RESULTS: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, α-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and α-KGDH E2 subunits. Accordingly, the production of (14)CO(2) by patient fibroblasts after incubation with (14C)glucose, (14C)butyrate or (14C)3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and α-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants. CONCLUSION: We report here a putative case of impaired free or H protein-derived lipoic acid attachment due to LIPT1 mutations as a cause of PDH and α-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies. BioMed Central 2013-12-17 /pmc/articles/PMC3905285/ /pubmed/24341803 http://dx.doi.org/10.1186/1750-1172-8-192 Text en Copyright © 2013 Soreze et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Soreze, Yohan
Boutron, Audrey
Habarou, Florence
Barnerias, Christine
Nonnenmacher, Luc
Delpech, Hélène
Mamoune, Asmaa
Chrétien, Dominique
Hubert, Laurence
Bole-Feysot, Christine
Nitschke, Patrick
Correia, Isabelle
Sardet, Claude
Boddaert, Nathalie
Hamel, Yamina
Delahodde, Agnès
Ottolenghi, Chris
de Lonlay, Pascale
Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
title Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
title_full Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
title_fullStr Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
title_full_unstemmed Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
title_short Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
title_sort mutations in human lipoyltransferase gene lipt1 cause a leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905285/
https://www.ncbi.nlm.nih.gov/pubmed/24341803
http://dx.doi.org/10.1186/1750-1172-8-192
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