Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

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 MateraIsabella 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, Tom De Koning, 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

研究成果: ジャーナルへの寄稿学術論文査読

29 被引用数 (Scopus)


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.

出版ステータス出版済み - 01-05-2021

All Science Journal Classification (ASJC) codes

  • 臨床神経学


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