Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy
(2021) In Brain : a journal of neurology 144(5). p.1451-1466- 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... (More)
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.
(Less)
- author
- publishing date
- 2021-04-15
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Brain : a journal of neurology
- volume
- 144
- issue
- 5
- pages
- 1451 - 1466
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85107848423
- pmid:33855352
- ISSN
- 1460-2156
- DOI
- 10.1093/brain/awab056
- language
- English
- LU publication?
- no
- id
- e33468d1-4c21-4369-8a04-d603d426524f
- date added to LUP
- 2021-04-19 15:56:41
- date last changed
- 2024-04-20 05:58:37
@article{e33468d1-4c21-4369-8a04-d603d426524f,
abstract = {{<p>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.</p>}},
author = {{Bonora, Elena and Chakrabarty, Sanjiban and Kellaris, Georgios and Tsutsumi, Makiko and Bianco, Francesca and Bergamini, Christian and Ullah, Farid and Isidori, Federica and Liparulo, Irene and Diquigiovanni, Chiara and Masin, Luca and Rizzardi, Nicola and Cratere, Mariapia Giuditta and Boschetti, Elisa and Papa, Valentina and Maresca, Alessandra and Cenacchi, Giovanna and Casadio, Rita and Martelli, Pierluigi and Matera, Ivana and Ceccherini, Isabella and Fato, Romana and Raiola, Giuseppe and Arrigo, Serena and Signa, Sara and Sementa, Angela Rita and Severino, Mariasavina and Striano, Pasquale and Fiorillo, Chiara and Goto, Tsuyoshi and Uchino, Shumpei and Oyazato, Yoshinobu and Nakamura, Hisayoshi and Mishra, Sushil K and Yeh, Yu-Sheng and Kato, Takema and Nozu, Kandai and Tanboon, Jantima and Morioka, Ichiro and Nishino, Ichizo and Toda, Tatsushi and Goto, Yu-Ichi and Ohtake, Akira and Kosaki, Kenjiro and Yamaguchi, Yoshiki and Nonaka, Ikuya and Iijima, Kazumoto and Mimaki, Masakazu and Kurahashi, Hiroki and Raams, Anja and MacInnes, Alyson and Alders, Mariel and Engelen, Marc and Linthorst, Gabor and de Koning, Tom and den Dunnen, Wilfred and Dijkstra, Gerard and van Spaendonck, Karin and van Gent, Dik C and Aronica, Eleonora M and Picco, Paolo and Carelli, Valerio and Seri, Marco and Katsanis, Nicholas and Duijkers, Floor A M and Taniguchi-Ikeda, Mariko and De Giorgio, Roberto}},
issn = {{1460-2156}},
language = {{eng}},
month = {{04}},
number = {{5}},
pages = {{1451--1466}},
publisher = {{Oxford University Press}},
series = {{Brain : a journal of neurology}},
title = {{Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy}},
url = {{http://dx.doi.org/10.1093/brain/awab056}},
doi = {{10.1093/brain/awab056}},
volume = {{144}},
year = {{2021}},
}