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LIG3 Variants Cause a Novel Mitochondrial Neurogastrointestinal Encephalomyopathy

By Malorye Branca on April, 19 2021


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Primary Reference: Bonara, E. et. Al. Brain, April 15, 2021.

Genes: LIG3

A team of scientists, led by Mariko Taniguchi-Ikeda from Fujita Health University Hospital, describes a set of seven patients with a novel mitochondrial disorder caused by biallelic variants in the gene that encodes the LIG3 protein. Their report provides a description of the patients' symptoms and the mutations' effects.

Mutations in genes including TYMP and POLG have been linked to several rare mitochondrial encephalomyopathies whose symptoms include abnormal gut motility.  There are three DNA ligases, but only ligase III (LIG3) has a mitochondrial splice variant that is crucial for mitochondrial health.  This team studied reduced LIG3 activity and its effects in seven patients from three different families.  All the patients showed gut dysmotility and neurologic manifestations signaling mitochondrial neurogastrointestinal encephalomyopathy.

DNA from each patient underwent whole exome sequencing.  The results were “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.”

The researchers say that this shows the LIG3 gene defect affects mtDNA maintenance, leading to DNA depletion (though without the accumulation of multiple deletions typical in other mitochondrial disorders).  They point to this as the cause of these patients’ conditions.


Additional resource:

Altered mitochondrial dynamics in motor neuron disease: An Emerging Perspective. Kodavati, M. et al. Cells, April 24, 2020.

This group’s studies detailed the involvement of specific defects in DNA break-ligation mediated by DNA ligase 3 (LIG3) in FUS-associated ALS. They note that this raised a question about the gene’s potential implication in mitochondrial DNA transactions, because LIG3 is essential for both mitochondrial DNA replication and repair. They write: “These new investigation avenues into the mechanistic role of mitochondrial dysfunction in MNDs are critical to identify therapeutic targets to alleviate mitochondrial toxicity and its consequences. In this article, we critically review recent advances in our understanding of mitochondrial dysfunction in diverse subgroups of MNDs and discuss challenges and future directions.”


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