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Title: Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25.
Austin Authors: Barbier, Mathieu;Bahlo, Melanie;Pennisi, Alessandra;Jacoupy, Maxime;Tankard, Rick M;Ewenczyk, Claire;Davies, Kayli C;Lino-Coulon, Patricia;Colace, Claire;Rafehi, Haloom;Auger, Nicolas;Ansell, Brendan R E;van der Stelt, Ivo;Howell, Katherine B;Coutelier, Marie;Amor, David J;Mundwiller, Emeline;Guillot-Noël, Lena;Storey, Elsdon;Gardner, R J McKinlay;Wallis, Mathew J ;Brusco, Alfredo;Corti, Olga;Rötig, Agnès;Leventer, Richard J;Brice, Alexis;Delatycki, Martin B ;Stevanin, Giovanni;Lockhart, Paul J;Durr, Alexandra
Affiliation: Clinical Genetics
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
Bruce Lefroy Centre, Murdoch Children's Research Institute, Melbourne, Victoria, Australia
Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
Donders Centre for Neuroscience, Faculty of Science, Radboud University, Nijmegen, The Netherlands
Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia
Murdoch Children's Research Institute, Melbourne, Victoria, Australia
Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia
School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
Victorian Clinical Genetics Service, Melbourne, Australia
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France
Clinical Genetics Group, University of Otago, Dunedin, New Zealand
Department of Medical Sciences, University of Torino, Torino, Italy
Necker Hospital, APHP, Reference Center for Mitochondrial Diseases, Genetics Department, Institut Imagine, University of Paris, Paris, France
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
Inserm UMR_S1163, Institut Imagine, Paris, France
Paris Sciences Lettres Research University, EPHE, Paris, France
Issue Date: Jul-2022
Date: 2022-05-07
Publication information: Annals of Neurology 2022; 92(1): 122-137
Abstract: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus. Whole-exome and whole-genome sequencing were performed in families linked to SCA25, including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology. The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 (PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25. An additional nonsense variant was detected in an unrelated individual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1-domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double-stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response. This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022;92:122-137.
DOI: 10.1002/ana.26366
Journal: Annals of Neurology
PubMed URL: 35411967
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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