Acta Neuropathologica

, Volume 125, Issue 4, pp 511–522

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

  • Elisa Teyssou
  • Takahiro Takeda
  • Vincent Lebon
  • Séverine Boillée
  • Brahima Doukouré
  • Guillaume Bataillon
  • Véronique Sazdovitch
  • Cécile Cazeneuve
  • Vincent Meininger
  • Eric LeGuern
  • François Salachas
  • Danielle Seilhean
  • Stéphanie Millecamps
Original Paper


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.


Motor neuron disease Familial and sporadic ALS Paget’s disease p62 Neuropathology FTLD–ALS 

Supplementary material

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Supplementary material 1 (JPG 536 kb)
401_2013_1090_MOESM2_ESM.doc (165 kb)
Supplementary material 2 (DOC 165 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elisa Teyssou
    • 1
  • Takahiro Takeda
    • 2
  • Vincent Lebon
    • 2
  • Séverine Boillée
    • 1
  • Brahima Doukouré
    • 2
  • Guillaume Bataillon
    • 2
  • Véronique Sazdovitch
    • 2
  • Cécile Cazeneuve
    • 3
  • Vincent Meininger
    • 4
  • Eric LeGuern
    • 1
    • 3
  • François Salachas
    • 1
    • 4
  • Danielle Seilhean
    • 1
    • 2
  • Stéphanie Millecamps
    • 1
    • 5
  1. 1.INSERM UMR_S975, CNRS UMR7225Université Pierre et Marie Curie-Sorbonne Universités, Hôpital Pitié-SalpêtrièreParisFrance
  2. 2.Département de NeuropathologieAssistance Publique Hôpitaux de Paris (AP-HP), Hôpital Pitié-SalpêtrièreParisFrance
  3. 3.Département de Génétique et Cytogénétique, APHPUnité Fonctionnelle de neurogénétique moléculaire et cellulaire, Hôpital Pitié-SalpêtrièreParisFrance
  4. 4.Fédération des Maladies du Système Nerveux, APHP, Centre de référence maladies rares SLA, Hôpital Pitié-SalpêtrièreParisFrance
  5. 5.Centre de Recherche de l’Institut du Cerveau et de la Moelle épinièreGroupe hospitalier Pitié-SalpêtrièreParisFrance

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