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The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level

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Abstract

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an inherited disorder of mitochondrial fatty acid oxidation associated with variations in the ACADS gene and variable clinical symptoms. In addition to rare ACADS inactivating variations, two common variations, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser), have been identified in patients, but these are also present in up to 14% of normal populations leading to questions of their clinical relevance. The common variant alleles encode proteins with nearly normal enzymatic activity at physiological conditions in vitro. SCAD enzyme function, however, is impaired at increased temperature and the tendency to misfold increases under conditions of cellular stress. The present study examines misfolding of variant SCAD proteins identified in patients with SCAD deficiency. Analysis of the ACADS gene in 114 patients revealed 29 variations, 26 missense, one start codon, and two stop codon variations. In vitro import studies of variant SCAD proteins in isolated mitochondria from SCAD deficient (SCAD−/−) mice demonstrated an increased tendency of the abnormal proteins to misfold and aggregate compared to the wild-type, a phenomenon that often leads to gain-of-function cellular phenotypes. However, no correlation was found between the clinical phenotype and the degree of SCAD dysfunction. We propose that SCAD deficiency should be considered as a disorder of protein folding that can lead to clinical disease in combination with other genetic and environmental factors.

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Acknowledgments

The following clinicians and researchers have—in addition to the authors—contributed by providing clinical information and biological material from the patients included in this study: Andrew Morris, London, UK; Klary Niezen-Koning, Groningen, The Netherlands; Eileen Naughton, Dublin, Ireland; Carsten Brandt, Kolding, Denmark; Mike Gibson, Oregon, USA; Bernhard Weschke, Berlin, Germany; Johannes Zschocke, Heidelberg, Germany; Andreas Schulze, Heidelberg, Germany; Alexander Lossos, Jerusalem, Israel; Gail Chuck, Cincinnati, USA; David Millington, North Carolina, USA; Ian Westphall, Odense Denmark; Peter Bækgaard, Gentofte, Denmark; Bwee Tien Poll-The, Amsterdam, The Netherland; Orly Elpeleg, Jerusalem, Israel; Søren Vidar Jacobsen, Esbjerg, Denmark; Sally Cress, Los Angeles, USA; Majed Dasouki, Missouri, USA; Kaj Lillquist, Hjørring, Denmark; Gerard Berry, Philadelphia, USA; Søren Anker Pedersen, Hvidovre, Denmark; Maria Kibæk, Odense, Denmark; Bruria Ben-Zeev, Tel Aviv, Israel; Michelle Fox, Los Angeles, USA; Martin Feurstein, Nykøbing Falster, Denmark; Karen Tilma, Hjorring, Denmark; Lise Bjerglund, Nykøbing Falster, Denmark; Rachel Strasberg, Israel; Bruno Leheup, Nancy, France, François Feillet, Nancy, France, Florence Rousselet, Nancy, France; Eric Vilain, Los Angeles, USA; Helene Ogier, Paris, France; Ruthie Shenhav, Israel; Dorit Lev, Israel; Rhona Jack, Seeatle, USA; Deborah Marsden, Boston, USA; Oliver Sass, Freiburg, Germany; Maria Luis Cardoso, Porto, Portugal; Jesper Andersen, Glostrup, Denmark; Tarja Linnankivi, Finland; Marius Dirdal, Herning, Denmark; Callum Wilson, Auckland, New Zealand; Natalia Blanc, Paris, France; Stanley Korman, Jerusalem, Israel; Niels Birkebæk, Aarhus, Denmark; Jens Erik Nielsen, Hvidovre, Denmark; Ilse Kern, Geneva, Switzerland; Charles Roe, Dallas, USA; Paula Morehart, Cincinnati, USA; Wendy Chung, Columbia, USA; Dwight Koeberl, Columbia, USA; Alexander Asamoah, Dallas, USA; Dries Dobbelaere, Lille, France; Jo Anne, Greenwood, USA; Thomas Dewald, Saarbrucken, Germany; Begona Merinero, Madrid, Spain. The investigations have been supported by The Danish Medical Research Council; Danish Human Genome Centre; Karen Elise Jensen Foundation; Aarhus University Hospital Research Initiative; Clinical Institute, Aarhus University Hospital; and Institute of Human Genetics, Aarhus University.

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Authors and Affiliations

  1. Research Unit for Molecular Medicine (MMF), Skejby and Faculty of Health Sciences, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200, Aarhus, Denmark

    Christina B. Pedersen, Vibeke Stenbroen, Margrethe Kjeldsen, Brage S. Andresen, Søren Vang, Peter Bross & Niels Gregersen

  2. Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark

    Steen Kølvraa

  3. Institute of Human Genetics, University of Aarhus, Aarhus, Denmark

    Steen Kølvraa, Thomas J. Corydon, Brage S. Andresen & Lars Bolund

  4. Medical Research Library, University of Aarhus, Aarhus, Denmark

    Agnete Kølvraa

  5. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany

    Regina Ensenauer

  6. Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

    Ingrid Tein

  7. Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA

    Dietrich Matern & Piero Rinaldo

  8. Centre de Biologie Est, CHU Lyon, Service Maladies Héréditaries du Métabolisme, Bron, France

    Christine Vianey-Saban

  9. Institut Bioquímica Clínica-CIBERER, Servei de Bioquímica i Genetica Molecular, Hospital Clínic, Barcelona, Spain

    Antonia Ribes

  10. Metabolic Unit, University Children’s Hospital, Freiburg, Germany

    Willy Lehnert

  11. Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark

    Ernst Christensen

  12. Department of Pediatrics, The Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jerry Vockley

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  1. Christina B. Pedersen
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  2. Steen Kølvraa
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  3. Agnete Kølvraa
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  4. Vibeke Stenbroen
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  6. Regina Ensenauer
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  7. Ingrid Tein
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  8. Dietrich Matern
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  9. Piero Rinaldo
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  10. Christine Vianey-Saban
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Correspondence to Niels Gregersen.

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Pedersen, C.B., Kølvraa, S., Kølvraa, A. et al. The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. Hum Genet 124, 43–56 (2008). https://doi.org/10.1007/s00439-008-0521-9

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