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Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1

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Abstract

We present clinical, neuroimaging, and molecular data on the identification of a new homozygous c.1783A>G (p.Thr595Ala) mutation in NDUFS1 in two inbred siblings with isolated complex I deficiency associated to a progressive cavitating leukoencephalopathy, a clinical and neuroradiological entity originally related to unknown defects of the mitochondrial energy metabolism. In both sibs, the muscle biopsy showed severe reduction of complex I enzyme activity, which was not obvious in fibroblasts. We also observed complex I dysfunction in a Neurospora crassa model of the disease, obtained by insertional mutagenesis, and in patient fibroblasts grown in galactose. Altogether, these results indicate that the NDUFS1 mutation is responsible for the disease and complex I deficiency. Clinical presentation of complex I defect is heterogeneous and includes an ample array of clinical phenotypes. Expanding the number of allelic variants in NDUFS1, our findings also contribute to a better understanding on the function of complex I.

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Acknowledgments

This research was supported by grants from the Portuguese Foundation for Science and Technology to AV, from the Canadian Institutes of Health Research (CIHR) to FEN, and from Telethon-Mitocon Project (Telethon GUP09004), Ricerca Finalizzata, and European Project LeukoTreat to EB and Ricerca Corrente to RC. MF holds a fellowship from the Portuguese Foundation for Science and Technology (FCT-SFRH/BD/28197/2006). Ana Castro is acknowledged for preparing the nuo78, his-3 strain by crossing the individual mutants.

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Authors and Affiliations

  1. Centro de Genética Médica Jacinto Magalhães, Instituto Nacional de Saúde Ricardo Jorge, Porto, Portugal

    Mariana Ferreira & Laura Vilarinho

  2. ICBAS Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Porto, Portugal

    Mariana Ferreira & Arnaldo Videira

  3. Unit of Molecular Medicine, Bambino Gesù Children’s Hospital, Rome, Italy

    Alessandra Torraco, Teresa Rizza, Fabiana Fattori, Maria Chiara Meschini, Fiorella Piemonte, Rosalba Carrozzo & Enrico Bertini

  4. Metabolic Unit, II Pediatric Division, Ospedale G. Di Cristina, Palermo, Italy

    Cinzia Castana

  5. Department of Biological Sciences, University of Alberta, Edmont, AB, Canada, T6G 2E9

    Nancy E. Go & Frank E. Nargang

  6. IBMC—Instituto de Biologia Molecular e Celular, Porto, Portugal

    Margarida Duarte & Arnaldo Videira

  7. Division of Metabolism, Bambino Gesù Children’s Hospital, Rome, Italy

    Carlo Dionisi-Vici

  8. UOC Neurogenetica e Malattie Neuromuscolari, IRCCS Fondazione Stella Maris, Pisa, Italy

    Filippo M. Santorelli

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  1. Mariana Ferreira
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Corresponding authors

Correspondence to Rosalba Carrozzo or Enrico Bertini.

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Supplementary Fig. 1

Luminometric measurement of ATP in controls and patient’s cultured fibroblasts growth either in regular medium (RM) or in medium supplemented for 24 h with galactose (GAL). In the presence of galactose, a specifically reduction (46%) in the ATP content was evident. In controls, the activity was similar in either condition used. (GIF 96 kb)

High resolution image (TIFF 6599 kb)

Supplementary Fig. 2

Alignment of the human protein NDUFS1 used the algorithm ClustalW at European Bioinformatics Institute (http://www2.ebi.ac.uk/clustalw). Residue number is indicated for the human sequence only. (GIF 163 kb)

High resolution image (TIFF 19783 kb)

Supplementary Table 1

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Ferreira, M., Torraco, A., Rizza, T. et al. Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novel mutation in NDUFS1 . Neurogenetics 12, 9–17 (2011). https://doi.org/10.1007/s10048-010-0265-2

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