Ataxia and cerebellar anomalies - narrow panelGene: LIG3
As only 1 family has signs of ataxia and the knockout mouse model recapitulated this phenotype this gene has been given an Amber rating on this panel.
Created: 19 May 2021, 12:53 p.m. | Last Modified: 19 May 2021, 12:53 p.m.
Panel Version: 2.183
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
Seven individuals from three unrelated families and functional data, variable ages of onset from early childhood to late adolescence.
Created: 10 May 2021, 10:06 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy
Tag watchlist tag was added to gene: LIG3.
Tag Q2_21_rating was removed from gene: LIG3.
gene: LIG3 was added gene: LIG3 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert Review Amber,Literature Q2_21_rating tags were added to gene: LIG3. Mode of inheritance for gene: LIG3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LIG3 were set to 33855352 Phenotypes for gene: LIG3 were set to gut dysmotility; spasticity; ataxia; repetitive behaviours; neurogenic bladder; macular degeneration; leukoencephalopathy; cerebellar atrophy; mitochondrial DNA depletion