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Neurodegenerative disease
Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis
  1. R Del Bo1,2,
  2. C Tiloca3,
  3. V Pensato4,
  4. L Corrado5,
  5. A Ratti1,3,
  6. N Ticozzi3,
  7. S Corti1,2,
  8. B Castellotti4,
  9. L Mazzini6,
  10. G Sorarù7,
  11. C Cereda8,
  12. S D'Alfonso5,
  13. C Gellera4,
  14. G P Comi1,2,
  15. V Silani1,3,
  16. The SLAGEN Consortium
  1. 1Department Neurological Sciences, ‘Dino Ferrari’ Center, Università degli Studi di Milano, Milan, Italy
  2. 2IRCCS Foundation Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
  3. 3Department Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
  4. 4Unit of Genetics of Neurodegenerative and Metabolic Disease, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta,’ Milan, Italy
  5. 5Department Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, ‘A. Avogadro’ University, Novara, Italy
  6. 6Department Neurology, A. Avogadro University and Maggiore della Carità Hospital, Novara, Italy
  7. 7Department Neurosciences, University of Padua, Padua, Italy
  8. 8Laboratory of Experimental Neurobiology, IRCCS National Neurological Institute ‘C. Mondino,’ Pavia, Italy
  1. Correspondence to Vincenzo Silani, Department of Neurology, Università degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, Milan 20149, Italy; vincenzo{at}


Background Optineurin (OPTN), a causative gene of hereditary primary open-angle glaucoma, has been recently associated with amyotrophic lateral sclerosis (ALS) with mainly autosomal recessive, but also dominant, traits. To further define the contribution of OPTN gene in ALS, we performed a mutational screening in a large cohort of Italian patients.

Methods A group of 274 ALS patients, including 161 familial (FALS) and 113 sporadic (SALS) cases, were screened for OPTN mutations by direct sequencing of its coding sequence. All patients fulfilled the El Escorial criteria for probable or definite ALS and were negative for mutations in SOD1, ANG, TARDBP and FUS/TLS genes.

Results The genetic analysis revealed six novel variants in both FALS and SALS patients, all occurring in an heterozygous state. We identified three missense (c.844A→C p.T282P, c.941A→T p.Q314L, c.1670A→C p.K557T), one nonsense (c.67G→T p.G23X) and two intronic mutations (c.552+1delG, c.1401+4A→G). The intronic c.552+1delG variant determined a splicing defect as demonstrated by mRNA analysis. All mutations were absent in 280 Italian controls and over 6800 worldwide glaucoma patients and controls screened so far. The clinical phenotype of OPTN-mutated patients was heterogeneous for both age of onset and disease duration but characterised by lower-limb onset and prevalence of upper motor neuron signs.

Conclusion In this cohort, OPTN mutations were present both in FALS (2/161), accounting for 1.2% cases, and in SALS patients (4/113), thereby extending the spectrum of OPTN mutations associated with ALS. The study further supports the possible pathological role of optineurin protein in motor neuron disease.

  • ALS
  • motor neuron disease
  • neurogenetics
  • genetics
  • clinical neurology

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  • RDB and CT contributed equally to the work.

  • Funding VP, BC, GS, CC, SD, CG, GPC and VS are financially supported by Italian Ministry of Health; CT, AR, NT, CG and VS by AriSLA (Grants EXOMEFALS and RBPALS); LC received a fellowship from ‘Amico Canobio’ Association.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by the Local ethics committees of each participating Institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.