PMID- 34119419 OWN - NLM STAT- MEDLINE DCOM- 20220107 LR - 20220107 IS - 1096-7206 (Electronic) IS - 1096-7192 (Linking) VI - 133 IP - 3 DP - 2021 Jul TI - A pathogenic HEXA missense variant in wild boars with Tay-Sachs disease. PG - 297-306 LID - S1096-7192(21)00702-2 [pii] LID - 10.1016/j.ymgme.2021.05.001 [doi] AB - Gangliosidoses are inherited lysosomal storage disorders caused by reduced or absent activity of either a lysosomal enzyme involved in ganglioside catabolism, or an activator protein required for the proper activity of a ganglioside hydrolase, which results in the intra-lysosomal accumulation of undegraded metabolites. We hereby describe morphological, ultrastructural, biochemical and genetic features of GM2 gangliosidosis in three captive bred wild boar littermates. The piglets were kept in a partially-free range farm and presented progressive neurological signs, starting at 6 months of age. Animals were euthanized at approximately one year of age due to their poor conditions. Neuropathogens were excluded as a possible cause of the signs. Gross examination showed a reduction of cerebral and cerebellar consistency. Central (CNS) and peripheral (PNS) nervous system neurons were enlarged and foamy, with severe and diffuse cytoplasmic vacuolization. Transmission electron microscopy (TEM) of CNS neurons demonstrated numerous lysosomes, filled by parallel or concentric layers of membranous electron-dense material, defined as membranous cytoplasmic bodies (MCB). Biochemical composition of gangliosides analysis from CNS revealed accumulation of GM2 ganglioside; furthermore, Hex A enzyme activity was less than 1% compared to control animals. These data confirmed the diagnosis of GM2 gangliosidosis. Genetic analysis identified, at a homozygous level, the presence of a missense nucleotide variant c.1495C > T (p Arg499Cys) in the hexosaminidase subunit alpha gene (HEXA), located within the GH20 hexosaminidase superfamily domain of the encoded protein. This specific HEXA variant is known to be pathogenic and associated with Tay-Sachs disease in humans, but has never been identified in other animal species. This is the first report of a HEXA gene associated Tay-Sachs disease in wild boars and provides a comprehensive description of a novel spontaneous animal model for this lysosomal storage disease. CI - Copyright (c) 2021. Published by Elsevier Inc. FAU - Bertani, Valeria AU - Bertani V AD - Department of Veterinary Science, University of Parma, Via Taglio, 8, 43100 Parma, Italy. Electronic address: bertani.valeria@gmail.com. FAU - Prioni, Simona AU - Prioni S AD - Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20129 Segrate, Italy. FAU - Di Lecce, Rosanna AU - Di Lecce R AD - Department of Veterinary Science, University of Parma, Via Taglio, 8, 43100 Parma, Italy. FAU - Gazza, Ferdinando AU - Gazza F AD - Department of Veterinary Science, University of Parma, Via Taglio, 8, 43100 Parma, Italy. FAU - Ragionieri, Luisa AU - Ragionieri L AD - Department of Veterinary Science, University of Parma, Via Taglio, 8, 43100 Parma, Italy. FAU - Merialdi, Giuseppe AU - Merialdi G AD - Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, Via Pietro Fiorini, 5, 40127, Bologna, Italy. FAU - Bonilauri, Paolo AU - Bonilauri P AD - Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna, Via Pietro Fiorini, 5, 40127, Bologna, Italy. FAU - Jagannathan, Vidhya AU - Jagannathan V AD - Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001 Bern, Switzerland. FAU - Grassi, Sara AU - Grassi S AD - Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20129 Segrate, Italy. FAU - Cabitta, Livia AU - Cabitta L AD - Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20129 Segrate, Italy. FAU - Paoli, Antonella AU - Paoli A AD - Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Florence, Italy. FAU - Morrone, Amelia AU - Morrone A AD - Molecular and Cell Biology Laboratory, Paediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, Florence, Italy; Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence, Italy. FAU - Sonnino, Sandro AU - Sonnino S AD - Department of Medical Biotechnology and Translational Medicine, University of Milano, Via Fratelli Cervi 93, 20129 Segrate, Italy. FAU - Drogemuller, Cord AU - Drogemuller C AD - Institute of Genetics, Vetsuisse Faculty, University of Bern, Bremgartenstrasse 109a, 3001 Bern, Switzerland. FAU - Cantoni, Anna Maria AU - Cantoni AM AD - Department of Veterinary Science, University of Parma, Via Taglio, 8, 43100 Parma, Italy. LA - eng PT - Journal Article DEP - 20210507 PL - United States TA - Mol Genet Metab JT - Molecular genetics and metabolism JID - 9805456 RN - EC 3.2.1.52 (Hexosaminidase A) SB - IM MH - Animals MH - Cerebellum/pathology MH - Disease Models, Animal MH - Female MH - Gangliosidoses, GM2/metabolism MH - *Genetic Variation MH - Hexosaminidase A/*genetics/metabolism MH - Male MH - *Mutation, Missense MH - Sus scrofa/*genetics MH - Tay-Sachs Disease/*genetics/pathology/*physiopathology MH - Whole Genome Sequencing OTO - NOTNLM OT - GM2 OT - HEXA OT - Lysosomal storage disease OT - Swine OT - Tay-Sachs disease OT - Whole-genome sequencing OT - Wild boar EDAT- 2021/06/14 06:00 MHDA- 2022/01/08 06:00 CRDT- 2021/06/13 20:34 PHST- 2020/10/23 00:00 [received] PHST- 2021/05/02 00:00 [revised] PHST- 2021/05/03 00:00 [accepted] PHST- 2021/06/14 06:00 [pubmed] PHST- 2022/01/08 06:00 [medline] PHST- 2021/06/13 20:34 [entrez] AID - S1096-7192(21)00702-2 [pii] AID - 10.1016/j.ymgme.2021.05.001 [doi] PST - ppublish SO - Mol Genet Metab. 2021 Jul;133(3):297-306. doi: 10.1016/j.ymgme.2021.05.001. Epub 2021 May 7.