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

Orphanet Journal of Rare Diseases

Pascale de Lonlay⁹  Chris Ottolenghi^1,10  Agnès Delahodde²  Yamina Hamel⁹  Nathalie Boddaert⁷  Claude Sardet⁶  Isabelle Correia⁴  Patrick Nitschke¹  Christine Bole-Feysot⁸  Laurence Hubert⁹  Dominique Chrétien⁵  Asmaa Mamoune⁹  Hélène Delpech⁶  Luc Nonnenmacher^1,10  Christine Barnerias³  Florence Habarou^1,10  Audrey Boutron⁴  Yohan Soreze⁹ 

[1] Plateforme Bioinformatique Paris Descartes, Université Paris Descartes, Hospital Necker Enfants Malades, Paris, France;Genetics and Microbiology Institute, Paris-Sud University, CNRS-UMR8621, Orsay, France;Neurology Unit, Hospital Necker Enfants Malades, Paris, France;Department of Biochemistry, Hospital Bicêtre, APHP, Le Kremlin Bicêtre, France;Imagine Institute, INSERM, 781, Paris, France;Department of Molecular Genetics, CNRS, UMR 5535, Montpellier, France;Department of radiology, Imagine Institute, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France;Genomic Core Facility of the Imagine Institute, University Paris Descartes, Hospital Necker Enfants Malades, Paris, France;Reference Center of Inherited Metabolic Diseases, Imagine Institute, University Paris Descartes, Hospital Necker Enfants Malades, APHP, Paris, France;Metabolic Biochemistry and INSERM U747, University Paris Descartes, Hospital Necker Enfants Malades, Paris, France

关键词: Alphaketoglutarate dehydrogenase lipoic acid;    Pyruvate dehydrogenase;    Leigh disease;    LIPT1;   

Others  :  863367
DOI  :  10.1186/1750-1172-8-192

 received in 2013-09-12, accepted in 2013-12-06,  发布年份 2013

【 摘 要 】

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 ¹⁴CO₂ by patient fibroblasts after incubation with ^14Cglucose, ^14Cbutyrate or ^14C3OHbutyrate 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.

【 授权许可】

   
2013 Soreze et al.; licensee BioMed Central Ltd.

【 图 表 】

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