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Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology

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Abstract

Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget’s disease and ALS patients carrying these mutations had both concomitant Paget’s disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.

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Acknowledgments

We are grateful to the patients and their families. We thank the Généthon cell and DNA bank (Evry, France) and the CRicm DNA and cell bank (Paris, France) for patients’ DNA and the genotyping and sequencing platform facilities of the ICM (Paris, France). This work was financed by the Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone (ARSla, France), the Association française contre les myopathies (AFM, France) and the Fondation NRJ-Institut de France (France). Protocols were approved by the Medical Research Ethics Committee of “Assistance Publique Hôpitaux de Paris” and all participants signed a consent form for the research.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. INSERM UMR_S975, CNRS UMR7225, Université Pierre et Marie Curie-Sorbonne Universités, Hôpital Pitié-Salpêtrière, Paris, France

    Elisa Teyssou, Séverine Boillée, Eric LeGuern, François Salachas, Danielle Seilhean & Stéphanie Millecamps

  2. Département de Neuropathologie, Assistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France

    Takahiro Takeda, Vincent Lebon, Brahima Doukouré, Guillaume Bataillon, Véronique Sazdovitch & Danielle Seilhean

  3. Département de Génétique et Cytogénétique, APHP, Unité Fonctionnelle de neurogénétique moléculaire et cellulaire, Hôpital Pitié-Salpêtrière, Paris, France

    Cécile Cazeneuve & Eric LeGuern

  4. Fédération des Maladies du Système Nerveux, APHP, Centre de référence maladies rares SLA, Hôpital Pitié-Salpêtrière, Paris, France

    Vincent Meininger & François Salachas

  5. Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière, Groupe hospitalier Pitié-Salpêtrière, 83, Bd de l’Hôpital, 75013, Paris, France

    Stéphanie Millecamps

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  1. Elisa Teyssou
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  2. Takahiro Takeda
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Correspondence to Stéphanie Millecamps.

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D. Seilhean and S. Millecamps contributed equally to this work.

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Teyssou, E., Takeda, T., Lebon, V. et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol 125, 511–522 (2013). https://doi.org/10.1007/s00401-013-1090-0

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