Identification of rare protein disulfide isomerase gene variants in amyotrophic lateral sclerosis patients.
Disruption of endoplasmic reticulum (ER) proteostasis is a salient feature of amyotrophic lateral sclerosis (ALS). Upregulation of ER foldases of the protein disulfide isomerase (PDI) family has been reported in ALS mouse models and spinal cord tissue and body fluids derived from sporadic ALS cases. Although in vitro studies suggest a neuroprotective role of PDIs in ALS, the possible contribution of genetic mutations of these ER foldases in the disease process remains unknown. Interestingly, intronic variants of the PDIA1 gene were recently reported as a risk factor for ALS. Here, we initially screened for mutations in two major PDI genes (PDIA1/P4HB and PDIA3/ERp57) in a US cohort of 96 familial and 96 sporadic ALS patients using direct DNA sequencing. Then, 463 familial and 445 sporadic ALS patients from two independent cohorts were also screened for mutations in these two genes using whole exome sequencing. A total of nine PDIA1 missense variants and seven PDIA3 missense variants were identified in 16 ALS patients. We have identified several novel and rare single nucleotide polymorphisms (SNPs) in both genes that are enriched in ALS cases compared with a large group of control subjects showing a frequency of around 1% in ALS cases. The possible biological and structural impact of these ALS-linked PDI variants is also discussed.
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Paloma
P
Gonzalez-Perez
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, University of Chile, Santiago, Chile; Center for Genomics and Bioinformatics, Faculty of Science, Universidad Mayor, Santiago, Chile.
Ute
U
Woehlbier
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Ru-Ju
RJ
Chian
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
Peter
P
Sapp
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 rue University, Montreal, QC H3A 2B4, Canada.
Guy A
GA
Rouleau
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 rue University, Montreal, QC H3A 2B4, Canada.
Claire S
CS
Leblond
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 rue University, Montreal, QC H3A 2B4, Canada.
Hussein
H
Daoud
Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 rue University, Montreal, QC H3A 2B4, Canada.
Patrick A
PA
Dion
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
John E
JE
Landers
Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile; Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, University of Chile, Santiago, Chile; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, USA. Electronic address: chetz@hsph.harvard.edu.
Claudio
C
Hetz
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. Electronic address: robert.brown@umassmed.edu.
Robert H
RH
Brown
D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D019704:Protein Disulfide-Isomerases
Amyotrophic lateral sclerosis; ER stress; ERp57; PDIA1; Protein disulfide isomerase