Expanding the Clinical Spectrum of LONP1-Related Mitochondrial Cytopathy

Abstract

Pathogenic variants in the LONP1 gene have been associated with CODAS syndrome (Cerebral, Ocular, Dental, Auricular, and Skeletal Anomalies Syndrome). A recent report identified the first newborn case with LONP1-related mitochondrial cytopathy due to a compound heterozygous pathogenic variant in LONP1 without features of CODAS. The proband had manifested with severe congenital lactic acidosis and profound multiple respiratory chain complex activity deficiencies associated with the quantitative loss of mtDNA copy number in muscle. A subsequent report identified two siblings with regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability, progressive cerebellar atrophy, where muscle biopsy showed an electron dense mitochondrial inclusions without ragged-red fibers and normal electron transport chain enzyme activities. Here, we report an additional case of autosomal recessive mitochondrial cytopathy due to a homozygous missense variant in LONP1 that was identified on whole exome sequencing (c.810G > A; p.D463N). The proband, a 20-year-old male born to consanguineous parents, presented with global developmental delay, emotional outbursts, speech and swallowing difficulties, hypotonia, and ataxia since childhood. Muscle biopsy showed massive granular bodies, increased oxidative stress, and autophagic block and reduced mitochondrial state 3 respiration. We have identified another case of LONP1-related mitochondrial cytopathy further confirming a neurological phenotype without CODAS features.

Genetic analysis of mitochondrial DNA copy number and associated traits identifies loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation, and reveals a causal association of mitochondrial function with mortality

“…This finding is consistent with a large body of work showing that mtDNA-CN measured in blood is associated with numerous aging-related phenotypes for which the primary tissue of interest is not blood (e.g. chronic kidney disease 13 , heart failure 11 , and diabetes 66 ). Also consistent with this finding is recent work demonstrating that mtDNA-CN measured in blood is associated with mtRNA expression across numerous non-blood tissues, suggesting a link between mitochondrial function measured in blood and other tissues 67 .…”

“…In addition to identifying the mtDNA depletion syndrome genes directly linked to mitochondrial DNA metabolic processes, DNA replication, and genome maintenance, we also identify genes which play a role in mitochondrial function. The top GWAS hit is a missense mutation in LONP1, which encodes a mitochondrial protease that has been shown to cause mitochondrial cytopathy and reduced respiratory chain activity 77,78 . Interestingly, this missense mutation was recently found to be associated with mitochondrial tRNA methylation levels .…”

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

“…In addition to identifying the mtDNA depletion syndrome genes directly linked to mitochondrial DNA metabolic processes, DNA replication, and genome maintenance, we also identify genes which play a role in mitochondrial function. The top GWAS hit is a missense mutation in LONP1 , which encodes a mitochondrial protease that has been shown to cause mitochondrial cytopathy and reduced respiratory chain activity (Hannah-Shmouni et al 2019 ; Grainha et al 2018 ). Interestingly, this missense mutation was recently found to be associated with mitochondrial tRNA methylation levels (Ali et al 2020 ).…”

The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass

“…In mice, the homozygous deletion of LonP1 causes early embryonic death [161]. In human skeletal muscle, the reduction of LonP1 activity results in electron-dense intra-mitochondrial accumulations, mitochondrial dysfunction, oxidative stress, and muscle weakness [162][163][164].…”