Possible mitochondrial disorder - nuclear genes

Gene: LIG3

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 1:12 p.m. | Last Modified: 1 Feb 2023, 1:12 p.m.

Panel Version: 2.5

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype in OMIM or Gene2Phenotype.

PMID:33855352. 3 unrelated families with 7 affected individuals. Clinical features of affected individuals resemble mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). All had severe dysmotility of the gut, leukoencephalopathy and/or progressive cortical atrophy. Cerebella atrophy was only seen in patients in family 3. Other neurological features were epilepsy, stroke-like episodes, migraine and developmental delay. 4 members from families 1 and 2 had macular degeneration, 1 member from family 3 had cataracts and hearing loss. Age of onset and disease severity differed, ranging from paediatric severe disease with premature death to adult cases. All affected members from the 3 families were compound heterozygous for different LIG3 variants.

LIG3 variants cause impared ligase activity, mtDNA depletion and mitochondrial dysfunction.

The authors also created a zebrafish model, which recapitulated the cerebellar phenotype (seen in mice) and eye defects and gut propulsion impairment (seen in patients). Knockdown of lig3 in zf also led to decrease in expression of mitochondrial markers.

Knocking out Lig3 in mice led to early embryonic lethality with mitochondrial dysfunction due to reduced mtDNA in the nervous system (PMID: 21390131); however, gut motility was not investigated in these mice.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

Created: 19 May 2021, 12:38 p.m. | Last Modified: 19 May 2021, 12:38 p.m.

Panel Version: 1.99

Green List (high evidence)

Seven individuals from three unrelated families and functional data, variable ages of onset from early childhood to late adolescence.
Sources: Literature

Created: 10 May 2021, 10:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy

Publications

• 33855352