Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

Research output: Contribution to journalArticle


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. Bonora et al. identify a new mitochondrial recessive disorder caused by biallelic variants in the LIG3 gene encoding DNA ligase III, which is responsible for mitochondrial DNA repair. Clinical signs include gut dysmotility and neurological features such as leucoencephalopathy, epilepsy and stroke-like episodes.


  • Elena Bonora
  • Sanjiban Chakrabarty
  • Georgios Kellaris
  • Makiko Tsutsumi
  • Francesca Bianco
  • Christian Bergamini
  • Farid Ullah
  • Federica Isidori
  • Irene Liparulo
  • Chiara Diquigiovanni
  • Luca Masin
  • Nicola Rizzardi
  • Mariapia Giuditta Cratere
  • Elisa Boschetti
  • Valentina Papa
  • Alessandra Maresca
  • Giovanna Cenacchi
  • Rita Casadio
  • Pierluigi Martelli
  • Ivana Matera
  • Isabella Ceccherini
  • Romana Fato
  • Giuseppe Raiola
  • Serena Arrigo
  • Sara Signa
  • Angela Rita Sementa
  • Mariasavina Severino
  • Pasquale Striano
  • Chiara Fiorillo
  • Tsuyoshi Goto
  • Shumpei Uchino
  • Yoshinobu Oyazato
  • Hisayoshi Nakamura
  • Sushil K Mishra
  • Yu-Sheng Yeh
  • Takema Kato
  • Kandai Nozu
  • Jantima Tanboon
  • Ichiro Morioka
  • Ichizo Nishino
  • Tatsushi Toda
  • Yu-Ichi Goto
  • Akira Ohtake
  • Kenjiro Kosaki
  • Yoshiki Yamaguchi
  • Ikuya Nonaka
  • Kazumoto Iijima
  • Masakazu Mimaki
  • Hiroki Kurahashi
  • Anja Raams
  • Alyson MacInnes
  • Mariel Alders
  • Marc Engelen
  • Gabor Linthorst
  • Wilfred den Dunnen
  • Gerard Dijkstra
  • Karin van Spaendonck
  • Dik C van Gent
  • Eleonora M Aronica
  • Paolo Picco
  • Valerio Carelli
  • Marco Seri
  • Nicholas Katsanis
  • Floor A M Duijkers
  • Mariko Taniguchi-Ikeda
  • Roberto De Giorgio
External organisations
  • University of Bologna
  • Fujita Health University
  • National University of Ireland Galway
  • Kobe university
  • Nihon University
  • University of Tokyo
  • Keio University
  • Hanyang University
  • University of Ferrara
  • Erasmus University Rotterdam
  • Duke University
  • Kyoto University
  • Saitama University
  • Tohoku University
  • Teikyo University
  • University of Amsterdam
  • University of Groningen
  • Gaslini Children's Hospital
  • University of California, Santa Barbara
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
Original languageEnglish
JournalBrain : a journal of neurology
Publication statusE-pub ahead of print - 2021 Apr 15
Publication categoryResearch
Externally publishedYes