DNA ligase proteins, which facilitate the formation of bonds between separate strands of DNA, play critical roles in the replication and maintenance of DNA. The human genome encodes three different DNA ligase proteins, but only one of those proteins--DNA ligase III (LIG3)--is expressed in mitochondria. LIG3 is therefore crucial for mitochondrial health, and inactivation of the homologous protein in mice causes profound mitochondrial dysfunction and early embryonic mortality.

In an article, a team of scientists describes a set of seven patients with a novel mitochondrial disorder caused by biallelic variants in the gene that encodes the LIG3 protein, called the "LIG3" gene. Their report provides a description of the patients' symptoms and a mechanistic exploration of the mutations' effects.

By performing whole-exome sequencing of DNA from the surviving patient, the authors discovered that the patient had inherited a p.P609L LIG3 variant from the father and a p.R811Ter LIG3 variant from the mother. The parents had kept the deceased brother's dried umbilical cord, and by analyzing DNA extracted from that source, the authors confirmed that the brother had carried the same LIG3 variants.

Having detected a novel genetic mitochondrial disorder, the authors wished to conduct further research by identifying other patients with pathogenic LIG3 variants. They could find no other such cases in Japan, but through a collaboration with researchers in Europe, they learned of two European families also affected by such variants. One was an Italian family in which three brothers had all inherited a p.K537N variant from their father and a p.G964R variant from their mother, and the other was a Dutch family in which two daughters had inherited a p.R267Ter variant from their father and a p.C999Y variant from their mother.

These patients experienced a complex syndrome involving severe gut dysmotility and neurologic abnormalities as the most consistently observed clinical signs. The neurologic abnormalities included leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. The prominent changes in the gut were decreased myenteric neuron counts and elevated fibrosis and elastin levels. Muscle pathology assessments revealed decreased staining intensities for cytochrome C oxidase.

To better characterize how the patients' LIG3 mutations could lead to such phenotypes, the researchers conducted experiments both in vitro and on zebrafish. The in vitro experiments with patient-derived fibroblasts showed that the mutations resulted in reduced LIG3 protein levels and diminished ligase activity. The consequent deficits in mitochondrial DNA maintenance would do much to explain the patients' presentations. 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. In describing the importance of these findings, the authors conclude, "Our study may facilitate efforts to diagnose patients with mitochondrial diseases. Our findings will also be beneficial to future investigations into the mitochondrial DNA repair system."

https://www.fujita-hu.ac.jp/en/news/kka9ar0000000ieb.html

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab056/6224919

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fbiallelic-variants-in&filter=22