Defective mitochondrial protease LonP1 can cause classical mitochondrial disease

Area of Science:

• Biochemistry
• Genetics
• Mitochondrial Biology

Background:

• LonP1 is a mitochondrial protease crucial for homeostasis.
• Pathogenic LONP1 defects cause CODAS syndrome with distinct skeletal and dental features.
• Mitochondrial diseases exhibit significant clinical heterogeneity.

Purpose of the Study:

• Investigate the genetic basis of a patient with Leigh syndrome and mitochondrial dysfunction.
• Determine the functional impact of novel LONP1 variants.
• Explore the phenotypic spectrum of LONP1-related disorders.

Main Methods:

• Whole exome sequencing to identify genetic variants.
• In vitro experiments to assess LonP1 mutant protein function (binding and degradation).
• Analysis of patient's clinical presentation, biochemical data, and MRI findings.

Main Results:

• Identified biallelic LONP1 variants (c.1693T>C and c.2197G>A) in a patient with Leigh syndrome.
• The p.(Tyr565His) LonP1 mutant impaired substrate binding and degradation.
• Compound heterozygosity for LONP1 variants resulted in severely depleted protease activity.

Conclusions:

• Pathogenic LONP1 variants can manifest as classical mitochondrial diseases, including Leigh syndrome.
• The identified LONP1 variants lead to severe oxidative phosphorylation defects.
• This expands the known clinical spectrum of LONP1-related disorders beyond CODAS syndrome.