In 2 sibs, born of unrelated Italian parents, with mitochondrial DNA depletion syndrome-20 (MTDPS20; 619780), manifest as mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), Invernizzi et al. (2021) identified compound heterozygous mutations in the LIG3 gene: a c.86G-A transition (c.86G-A, NM_013975.4), resulting in a trp29-to-ter (W29X) substitution in the mitochondrial targeting sequence, and a deep intronic G-to-A transition (c.1611+209G-A), resulting in aberrant splicing of exon 9 and premature termination (Ala539Ter). The mutations, which were found by whole-exome and whole-genome sequencing, segregated with the disorder in the family. LIG3 transcripts were reduced and protein levels were about 56% of controls. Patient fibroblasts showed impaired recovery of induced mtDNA depletion. The authors noted that the LIG3 gene contains 2 putative start codons, with the upstream ATG used for the mitochondrial isoform. Thus, the nuclear isoform may still be translated from the allele with the W29X mutation; the splice site mutation disrupts both isoforms. The patients had neonatal fatal myopathy and evidence of mitochondrial dysfunction.
