Rare Genetic Mitochondrial Disease Discovered via Whole-Exome Sequencing

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Mitochondrion
[Source: iLexx/Getty Images]

A team of European and Japanese scientists, led by Mariko Taniguchi-Ikeda, Ph.D., from Fujita Health University Hospital, have described a set of seven patients with a novel mitochondrial disorder caused by biallelic variants in ligase III (LIG3)—a ligase involved in DNA replication and repair. LG3 plays a role in mitochondrial DNA (mtDNA) maintenance and repair and previous studies have shown inactivation of the LIG3 gene has resulted in mitochondrial dysfunction.

The findings were published in the journal Brain in a paper titled, “Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.”

“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,” wrote the researchers. “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.”

“I wanted to make a distinct clinical and genetic diagnosis for the affected patient,” Taniguchi-Ikeda explained, “because his elder brother had passed away and the surviving boy was referred to my outpatient ward for detailed genetic tests.”

Whole-exome sequencing of DNA from the surviving patient revealed the patient had inherited a p.P609L LIG3 variant from his father and a p.R811Ter LIG3 variant from his mother. The parents had kept the deceased brother’s dried umbilical cord, and by analyzing DNA extracted from it, the researchers confirmed that the brother had carried the same LIG3 variants.

To investigate further, researchers from Fujita Health University collaborated with researchers in Europe, including Elena Bonora, PhD, associate professor, University of Bologna and Roberto De Giorgio, PhD, associate professor, University of Ferrara, found two European families also affected by such variants.

The patients experienced a syndrome involving severe gut dysmotility and neurologic abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder.

The researchers conducted experiments both in vitro and on zebrafish to observe further. The in vitro experiments with patient-derived fibroblasts showed that the mutations resulted in reduced LIG3 protein levels and diminished ligase activity. Experiments with zebrafish showed that disrupting the LIG3 gene produced brain alterations and gut transit impairments analogous to those observed in the patients.

The study brings to light a novel disorder resulting from disruption of a gene that plays a critical role in the maintenance of mitochondrial DNA. The study “identifies 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,” concluded the researchers.

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