2. Academic Validation
  3. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

  • Brain. 2021 Jun 22;144(5):1451-1466. doi: 10.1093/brain/awab056.
Elena Bonora 1,  Sanjiban Chakrabarty 2,  Georgios Kellaris 3,  Makiko Tsutsumi 4,  Francesca Bianco 1,  Christian Bergamini 5,  Farid Ullah 3,  Federica Isidori 1,  Irene Liparulo 5,  Chiara Diquigiovanni 1,  Luca Masin 5,  Nicola Rizzardi 5,  Mariapia Giuditta Cratere 1 6,  Elisa Boschetti 1,  Valentina Papa 7,  Alessandra Maresca 8,  Giovanna Cenacchi 7,  Rita Casadio 9,  Pierluigi Martelli 9,  Ivana Matera 10,  Isabella Ceccherini 10,  Romana Fato 5,  Giuseppe Raiola 11,  Serena Arrigo 10,  Sara Signa 10,  Angela Rita Sementa 10,  Mariasavina Severino 10,  Pasquale Striano 10,  Chiara Fiorillo 10,  Tsuyoshi Goto 12,  Shumpei Uchino 13 14,  Yoshinobu Oyazato 15,  Hisayoshi Nakamura 16,  Sushil K Mishra 17,  Yu-Sheng Yeh 12,  Takema Kato 4,  Kandai Nozu 18,  Jantima Tanboon 16,  Ichiro Morioka 19,  Ichizo Nishino 16,  Tatsushi Toda 20,  Yu-Ichi Goto 21,  Akira Ohtake 22,  Kenjiro Kosaki 23,  Yoshiki Yamaguchi 24,  Ikuya Nonaka 16,  Kazumoto Iijima 18,  Masakazu Mimaki 13,  Hiroki Kurahashi 4,  Anja Raams 2,  Alyson MacInnes 25,  Mariel Alders 26,  Marc Engelen 27,  Gabor Linthorst 25,  Tom de Koning 28,  Wilfred den Dunnen 29,  Gerard Dijkstra 30,  Karin van Spaendonck 26,  Dik C van Gent 2,  Eleonora M Aronica 31,  Paolo Picco 10,  Valerio Carelli 7 8,  Marco Seri 1,  Nicholas Katsanis 3,  Floor A M Duijkers 26,  Mariko Taniguchi-Ikeda 4 18 32,  Roberto De Giorgio 33
Affiliations

Affiliations

  • 1 Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, 40138, Italy.
  • 2 Department of Molecular Genetics, Erasmus MC, Rotterdam, 3000 CA, The Netherlands.
  • 3 Center for Human Disease Modeling, Duke University, Durham, NC 27710, USA.
  • 4 Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Aichi, 470-1192, Japan.
  • 5 Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy.
  • 6 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, 20132, Italy.
  • 7 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, 40123, Italy.
  • 8 IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, 40139, Italy.
  • 9 Biocomputing Group, Department of Biological, Geological, Environmental Sciences, University of Bologna, Bologna, 40126, Italy.
  • 10 IRCCS Istituto Giannina Gaslini, Genova, 16128, Italy.
  • 11 Department of Paediatrics, Pugliese-Ciaccio Hospital, Catanzaro, 88100, Italy.
  • 12 Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, 611-0011, Japan.
  • 13 Department of Pediatrics, Teikyo University School of Medicine, Tokyo, 173-8605, Japan.
  • 14 Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
  • 15 Department of Pediatrics, Kakogawa Central City Hospital, Kakogawa, Hyogo, 675-8611, Japan.
  • 16 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan.
  • 17 Glycoscience Group, National University of Ireland, Galway, H91 CF50, Ireland.
  • 18 Department of Pediatrics, Kobe University Graduate School of Medicine, Hyogo, 650-0017, Japan.
  • 19 Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, 173-8610, Japan.
  • 20 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
  • 21 Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, 187-8502, Japan.
  • 22 Department of Pediatrics & Clinical Genomics, Faculty of Medicine, Saitama Medical University, Saitama, 350-0495, Japan.
  • 23 Center for Medical Genetics, Keio University School of Medicine, Tokyo, 160-8582, Japan.
  • 24 Laboratory of Pharmaceutical Physical Chemistry, Tohoku Medical and Pharmaceutical University, Miyagi, 981-8558, Japan.
  • 25 Department of Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands.
  • 26 Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands.
  • 27 Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands.
  • 28 Department of Metabolic Diseases, UMCG, Groningen, 9700 RB, The Netherlands.
  • 29 Department of Pathology, UMCG, Groningen, 9700 RB, The Netherlands.
  • 30 Department of Gastroenterology, UMCG, Groningen, 9700 RB, The Netherlands.
  • 31 Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, 1100 DD, The Netherlands.
  • 32 Department of Clinical Genetics, Fujita Health University Hospital, Aichi, 470-1192, Japan.
  • 33 Department of Morphology, Surgery and Experimental Medicine, St. Anna Hospital, University of Ferrara, Ferrara, 44124, Italy.
PMID: 33855352 DOI: 10.1093/brain/awab056
Abstract

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.

Keywords

LIG3; CIPO; MNGIE; mtDNA repair; mtDNA replication.

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