Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice

Area of Science:

• Mitochondrial biology
• Neurogenetics
• Rare disease research

Background:

• NUBPL variants are linked to complex I deficiency mitochondrial disease, causing severe neurological problems like seizures and intellectual disability.
• This rare condition has only 19 reported cases globally, with no available treatments.
• Understanding NUBPL variant pathogenesis is crucial for developing therapeutic strategies.

Discussion:

• A patient-specific NUBPL variant (c.311T>C; p.L104P) was introduced into mice to model the disease.
• Homozygous knock-in mice exhibited embryonic lethality (E10.5), suggesting the variant acts as a hypomorph.
• Hemizygous mice showed no significant behavioral or pathological changes related to alpha-synuclein or oxidative stress, despite a known link between NUBPL and Parkinson's disease.

Key Insights:

• Homozygous NUBPL variants, like null alleles, result in lethality.
• Heterozygous NUBPL variant carriers are phenotypically and neuropathologically normal.
• The p.L104P variant functions as a hypomorph, impairing NUBPL function but not causing complete loss.

Outlook:

• A tissue-specific knockout strategy is proposed for creating a viable mouse model.
• This model will facilitate future mechanistic and translational studies for NUBPL-associated complex I deficiency.
• Further research is needed to explore therapeutic interventions for this rare mitochondrial disorder.