Exome Sequencing Reveals Novel Mitochondrial Disorder

DNA replication and repair involves three distinct DNA.ligases. Among the three ligase 3 is the only ligase of the three present in the Mitochondrial, where it plays a role in Mitochondrial DNA maintenance and repair. Many studies have shown inactivation of the ligase 3 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.”

The team included scientists from Europe and Japan. It was led by Mariko Taniguchi-Ikeda, PhD, from Fujita Health University Hospital, who described a set of seven patients with a novel mitochondrial disorder caused by biallelic variants in Ligase 3. The findings provide insights into future investigations into the mitochondrial DNA repair system.

The researchers said that the Abnormal gut motility is a feature of several  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 3, has a Mitochondrial splice variant and is crucial for health. We investigated the effect of reduced ligase 3 activity and which resulted in the 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.

Taniguchi-Ikeda explained that the researchers wanted to make a distinct clinical and genetic diagnosis for the affected patient. The researchers h 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 Ligase 3 variant from his father and a p.R811Ter Ligase 3 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 Ligase 3 variants.The patients experienced a syndrome involving severe gut dysmotility and neurologic abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder.