Abstract | BACKGROUND: METHODS: 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.
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Authors | Yohan Soreze, Audrey Boutron, Florence Habarou, Christine Barnerias, Luc Nonnenmacher, Hélène Delpech, Asmaa Mamoune, Dominique Chrétien, Laurence Hubert, Christine Bole-Feysot, Patrick Nitschke, Isabelle Correia, Claude Sardet, Nathalie Boddaert, Yamina Hamel, Agnès Delahodde, Chris Ottolenghi, Pascale de Lonlay |
Journal | Orphanet journal of rare diseases
(Orphanet J Rare Dis)
Vol. 8
Pg. 192
(Dec 17 2013)
ISSN: 1750-1172 [Electronic] England |
PMID | 24341803
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amino Acids
- Carrier Proteins
- NFU1 protein, human
- Thioctic Acid
- Ketone Oxidoreductases
- pyruvate dehydrogenase (NADP+)
- Pyruvate Dehydrogenase (Lipoamide)
- pyruvate dehydrogenase E1alpha subunit
- Ketoglutarate Dehydrogenase Complex
- Acyltransferases
- lipoyltransferase I
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Topics |
- Acyltransferases
(genetics)
- Amino Acids
(blood, cerebrospinal fluid, urine)
- Carrier Proteins
(genetics)
- Cells, Cultured
- Fibroblasts
(metabolism)
- Humans
- Immunoblotting
- Ketoglutarate Dehydrogenase Complex
(deficiency, genetics)
- Ketone Oxidoreductases
(deficiency, genetics)
- Leigh Disease
(blood, genetics, urine)
- Pyruvate Dehydrogenase (Lipoamide)
(genetics)
- Thioctic Acid
(blood, cerebrospinal fluid, urine)
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