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J. Biol. Chem., Vol. 279, Issue 44, 45951-45956, October 29, 2004

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A Frameshift Deletion in Peripherin Gene Associated with Amyotrophic Lateral Sclerosis^*

François Gros-Louis, Roxanne Larivière¶, Geneviève Gowing¶, Sandra Laurent, William Camu||**, Jean-Pierre Bouchard, Vincent Meininger, Guy A. Rouleau, and Jean-Pierre Julien¶¶¶

From the Centre for Research in Neuroscience, McGill University Health Centre, Montreal General Hospital Research Institute, Montreal, Québec H3G 1A4, Canada, the ^¶Centre de Recherche du Centre Hospitalier de l'Université Laval, Département d'anatomie et physiologie de l'Université Laval, 2795 boul. Laurier, Québec G1V 4G2, Canada, the ^||Unité de Neurologie Comportementale et Dégénérative Molecular Unit, INSERM V336, Institute of Biology, 34295 Montpellier Cedex 5, France, the ^**Clinique du Motoneurone, Service d'Explorations Neurologiques, Hôpital Guy de Chauliac, 34295 Montpellier Cedex 5, France, the Federation of Neurology Mazarin, Hôpital Pitié Salpetrière Paris France, 47–83, Bd. de L'Hôpital, 75651 Paris, Cedex 13, France, and the Département des Sciences Neurologiques, Centre Hospitalier Affilié Universitaire de Québec, Pavillion Enfant-Jésus, Québec G1J 1Z4, Canada

Peripherin is a neuronal intermediate filament associated with inclusion bodies in motor neurons of patients with amyotrophic lateral sclerosis (ALS). A possible peripherin involvement in ALS pathogenesis has been suggested based on studies with transgenic mouse overexpressors and with a toxic splicing variant of the mouse peripherin gene. However, the existence of peripherin gene mutations in human ALS has not yet been documented. Therefore, we screened for sequence variants of the peripherin gene (PRPH) in a cohort of ALS patients including familial and sporadic cases. We identified 18 polymorphic variants of PRPH detected in both ALS and age-matched control populations. Two additional PRPH variants were discovered in ALS cases but not in 380 control individuals. One variant consisted of a nucleotide insertion in intron 8 (PRPH^{IVS8–36insA}), whereas the other one consisted of a 1-bp deletion within exon 1 (PRPH^228delC), predicting a truncated peripherin species of 85 amino acids. Remarkably, expression of this frameshift peripherin mutant in SW13 cells resulted in disruption of neurofilament network assembly. These results suggest that PRPH mutations may be responsible for a small percentage of ALS, cases and they provide further support of the view that neurofilament disorganization may contribute to pathogenesis.

Received for publication, July 19, 2004

^* This work was supported by the NINDS National Institutes of Health, by the Muscular Dystrophy Association, and by the ALS Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Canadian Institute for Health Research.

^¶¶ A Canada Research Chair in Neurodegeneration. To whom correspondence should be addressed: Centre de Recherche de CHUL, 2705 boul. Laurier, Québec G1V 4G2, Canada. E-mail: Jean-Pierre.Julien{at}crchul.ulaval.ca.

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