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Matalonga Borrel, LesleyAuthorNavarro Colas, SalvadorAuthorTort, FAuthorFerrer-Cortes, XAuthorBujan, NAuthorArias, AAuthorGarcia-Villoria, JuditAuthorBriones, PAuthorRibes, ACorresponding Author

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January 7, 2014
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Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated ketoacid dehydrogenase complexes

Publicated to:Human Molecular Genetics. 23 (7): 1907-1915 - 2014-04-01 23(7), DOI: 10.1093/hmg/ddt585

Authors: Tort, Frederic; Ferrer-Cortes, Xenia; Thio, Marta; Navarro-Sastre, Aleix; Matalonga, Leslie; Quintana, Ester; Bujan, Nuria; Arias, Angela; Garcia-Villoria, Judit; Acquaviva, Cecile; Vianey-Saban, Christine; Artuch, Rafael; Garcia-Cazorla, Angels; Briones, Paz; Ribes, Antonia

Affiliations

CHU Lyon, Ctr Biol Est, Serv Malad Hereditaires Metab, F-69500 Bron, France - Author
CIBER Enfermedades Raras CIBERER, Barcelona, Spain - Author
CSIC, Barcelona, Spain - Author
Hosp Clin Barcelona, IDIBAPS, Serv Bioquim & Genet Mol, Seccio Errors Congenits Metab, Barcelona 08028, Spain - Author
Hosp St Joan de Deu, Dept Bioquim, Esplugas de Llobregat 08950, Spain - Author
Hosp St Joan de Deu, Serv Neurol, Esplugas de Llobregat 08950, Spain - Author
Institut d'Investigacions Biomèdiques August Pi i Sunyer - IDIBAPS - Author
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Abstract

Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1, BOLA3, LIAS and IBA57 have been identified in patients with deficient lipoic acid-dependent enzymatic activities and defects in the assembly and activity of the mitochondrial respiratory chain complexes. Here, we report a patient with an early onset fatal lactic acidosis presenting a biochemical phenotype compatible with a combined defect of pyruvate dehydrogenase (PDHC) and 2-ketoglutarate dehydrogenase (2-KGDH) activities, which suggested a deficiency in lipoic acid metabolism. Immunostaining analysis showed that lipoylated E2-PDH and E2-KGDH were extremely reduced in this patient. However, the absence of glycine elevation, the normal activity of the glycine cleavage system and the normal lipoylation of the H protein suggested a defect of lipoic acid transfer to particular proteins rather than a general impairment of lipoic acid biosynthesis as the potential cause of the disease. By analogy with yeast metabolism, we postulated LIPT1 as the altered candidate gene causing the disease. Sequence analysis of the human LIPT1 identified two heterozygous missense mutations (c.212C>T and c.292C>G), segregating in different alleles. Functional complementation experiments in patient's fibroblasts demonstrated that these mutations are disease-causing and that LIPT1 protein is required for lipoylation and activation of 2-ketoacid dehydrogenases in humans. These findings expand the spectrum of genetic defects associated with lipoic acid metabolism and provide the first evidence of a lipoic acid transfer defect in humans.

Keywords

biogenesisdeficiencydiagnosisescherichia-colilipoic acidmetabolismnfu1Acidosis, lacticAcyltransferasesAmino acid metabolism, inborn errorsAnimalsCells, culturedChlorocebus aethiopsCos cellsEnergy metabolismFemaleHumansInfant, newbornKetoglutarate dehydrogenase complexKetoglutaric acidsLipoylationLipoyltransferase iMitochondriaMultiple respiratory-chainMutation, missenseOxo-acid-lyasesPyruvate dehydrogenase complexThioctic acid

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Human Molecular Genetics due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2014, it was in position 17/167, thus managing to position itself as a Q1 (Primer Cuartil), in the category Genetics & Heredity.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.39. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Field Citation Ratio (FCR) from Dimensions: 6.59 (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-06, the following number of citations:

  • WoS: 59
  • Scopus: 34
  • Europe PMC: 42

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-06:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 45.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 47 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 0.5.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (Tort Escalé, Frederic) and Last Author (Ribes Rubio, Antonia).

the author responsible for correspondence tasks has been Ribes Rubio, Antonia.