Investigation of a case of encephalopathy, hypotonia and severe developmental delay resulted in identification of biallelic variants in the OXA1L gene; OXA1L encodes an evolutionarily conserved protein that is localized to the inner mitochondrial membrane. Other genes involved in mitochondrial metabolism were assessed, but no other pathogenic variants were identified. One of the OXA1L variants causes a frameshift and the other affects splicing, and thus both are likely to be loss-of-function alleles. The family's pedigree is consistent with autosomal recessive inheritance. There is a single orthologous gene in Drosophila, which shares the genetic symbol of the human gene, OXA1L, and for which RNAi targeting constructs have been generated.
The human OXA1L gene has not been introduced into flies.
To support the hypothesis that OXPHOS defects seen in patient fibroblasts were caused by the OXA1L variants, Drosophila adults with knockdown of Dmel\OXA1L effected by RNAi were characterized for OXPHOS function. Of particular interest was whether mitochondrial complex IV was affected. Although the representative complex I subunit was most affected, steady-state levels of representative subunits from all OXPHOS complexes were decreased in OXA1L-depleted flies, including complex IV. Mitochondrial respiration was severely affected and the animals died shortly after eclosion.
[updated Mar. 2019 by FlyBase; FBrf0222196]
Based on a single described case, a child who exhibited severe encephalopathy and hypotonia at birth with subsequent neurodevelopmental delay, achieving independent sitting at 12 months, but never being able to stand or walk. At 4 years, continued hypotonia, intellectual disability and lack of language skills were noted (FBrf0240558).
Data are consistent with recessive inheritance (FBrf0240558).
OXA1L encodes an evolutionarily conserved protein that is localized to the inner mitochondrial membrane. It is required for the insertion of integral membrane proteins into the mitochondrial inner membrane, for the activity and assembly of cytochrome oxidase, and for the correct biogenesis of ATP synthase and complex I in mitochondria. [Gene Cards, OXA1L; 2019.03.13]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human OXA1L (1 Drosophila to 1 human). Dmel\OXA1L shares 34% identity and 55% similarity with the human gene.
