A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient Lucia Corrado a, * 1 , Yari Carlomagno a,1 , Luca Falasco a , Simona Mellone a , Michela Godi a , Emanuela Cova b , Cristina Cereda b , Lucia Testa c , Letizia Mazzini c , Sandra D’Alfonso a a Department Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Italy b Laboratory of Experimental Neurobiology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Neurological Institute “C. Mondino”, Pavia, Italy c Department of Neurology, “A. Avogadro” University, Maggiore della Carita Hospital, Novara, Italy Received 9 September 2009; received in revised form 7 January 2010; accepted 16 February 2010 Abstract Motor neurons in amyotrophic lateral sclerosis (ALS) are characterized by the presence of inclusion bodies composed of intermediate filament (IF) proteins. Peripherin protein is as components of these inclusions and rare mutations in peripherin gene (PRPH) were identified in sporadic ALS cases. The aim of this study was to further define the spectrum of PRPH mutations in a cohort of 122 Italian ALS patients. We screened the coding sequence, the exon/intron boundaries, and the 5=–3= un-translated regions (UTRs) in 122 ALS patients. Eighteen sequence variations were detected. Seven variants were not identified in a panel of at least 245 matched controls, including 2 missense variations, namely p.R133P and p.D141Y, each identified in one heterozygous patient. p.R133P was newly identified whereas p.D141Y was previously described in one homozygous sporadic ALS patient. These 2 variants were predicted to have a deleterious effect on protein structure or function. This work contributes to determine the role of PRPH gene variants in ALS. Further studies are necessary to define the mechanisms through which the mutant peripherin could cause ALS phenotype. © 2011 Elsevier Inc. All rights reserved. Keywords: Amyotrophic lateral sclerosis; Mutation; Peripherin; PRPH gene; Sporadic 1. Introduction Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that affects motor neurons of the brain stem and spinal cord, resulting in paralysis and death within 2–5 years. Although most cases of ALS are sporadic (SALS), some families demonstrate a clinically indistin- guishable form of ALS with clear Mendelian inheritance and high penetrance (FALS). Pathogenic mutations in the SOD1 gene have been found in approximately 20% of all FALS pedigrees (Rosen et al., 1993), while variants in the TARDBP gene account for additional  5% of cases (Lagier-Tourenne and Cleveland, 2009). Moreover, at least 9 disease loci and pathogenic mutations in 5 other genes (ALS2, SETX, VAPB, DNCT1, and ANG) have been de- scribed in isolated families (Beleza-Meireles and Al- Chalabi, 2009; Pasinelli and Brown, 2006). Recently, mu- tations in the FUS gene, located on chromosome 16, have been identified in  5% of FALS patients that tested neg- ative for SOD1 and TARDBP mutations (Kwiatkowski et al., 2009; Vance et al., 2009). A hallmark of motor neurons in ALS is the presence of inclusion bodies composed of intermediate filament (IF) proteins in the pericaryon and axon of motor neurons. Neurofilament and peripherin pro- teins were identified as components of these inclusions. Peripherin (PRPH) is associated with ubiquitinated inclu- sions, specifically round inclusions and Lewy body-like inclusions, hyaline conglomerate inclusions, as well as with axonal spheroids, which occur in proximal axons of dis- eased motor neurons (Corbo and Hays, 1992; He and Hays, * Corresponding author at: University of Eastern Piedmont, Department Medical Sciences, Via Solaroli, 17, 28100 Novara, Italy. Tel: 03 +39 0321 660606. E-mail address: lucia.corrado@med.unipmn.it (L. Corrado). 1 These authors contributed equally to this work. Neurobiology of Aging 32 (2011) 552.e1–552.e6 www.elsevier.com/locate/neuaging 0197-4580/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2010.02.011