Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias

Authors

  • Claudia Cagnoli,

    1. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    2. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
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  • Giovanni Stevanin,

    1. INSERM, U975 (formerly U679), Paris, France
    2. UPMC University Paris 6, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, CNRS 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France
    3. APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
    4. Ecole Pratique des Hautes Etudes (EPHE), Paris, France
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  • Alessandro Brussino,

    1. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    2. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
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  • Marco Barberis,

    1. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    2. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
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  • Cecilia Mancini,

    1. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    2. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
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  • Russell L. Margolis,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Susan E. Holmes,

    1. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Marcello Nobili,

    1. Division of Neurology, Martini Hospital, Torino, Italy
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  • Sylvie Forlani,

    1. INSERM, U975 (formerly U679), Paris, France
    2. UPMC University Paris 6, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, CNRS 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France
    3. APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Sergio Padovan,

    1. IBB-CNR, c/o Molecular Biotecnology Center University of Torino, Torino, Italy
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  • Patrizia Pappi,

    1. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
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  • Cécile Zaros,

    1. APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Isabelle Leber,

    1. INSERM, U975 (formerly U679), Paris, France
    2. UPMC University Paris 6, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, CNRS 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France
    3. APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Pascale Ribai,

    1. INSERM, U975 (formerly U679), Paris, France
    2. UPMC University Paris 6, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, CNRS 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France
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  • Luisa Pugliese,

    1. S.A.F.AN. BIOINFORMATICS, Torino, Italy
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  • Corrado Assalto,

    1. S.A.F.AN. BIOINFORMATICS, Torino, Italy
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  • Alexis Brice,

    1. INSERM, U975 (formerly U679), Paris, France
    2. UPMC University Paris 6, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, CNRS 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France
    3. APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Nicola Migone,

    1. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    2. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
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  • Alexandra Dürr,

    1. INSERM, U975 (formerly U679), Paris, France
    2. UPMC University Paris 6, UMR_S975, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, CNRS 7225, Pitié-Salpêtrière Hospital, 75013 Paris, France
    3. APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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  • Alfredo Brusco

    Corresponding author
    1. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
    2. S.C. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy
    • Dipartimento di Genetica Biologia e Biochimica, Università degli Studi di Torino, via Santena 19, 10126, Torino, Italy
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  • Communicated by Mireille Claustres

Abstract

Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ∼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ∼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15–16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc.

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