LONP1 – CODAS Syndrome

LONP1 encodes a homohexameric ATP-dependent mitochondrial matrix protease that mediates protein quality control, respiratory-complex assembly and stress responses. Biallelic pathogenic variants in LONP1 underlie CODAS (cerebral, ocular, dental, auricular and skeletal anomalies) syndrome, a rare autosomal recessive multi-system developmental disorder characterized by distinctive craniofacial and skeletal features. The association has been reported in multiple cohorts with functional validation confirming a primary defect in ATP-dependent proteolysis.

In a landmark study, 10 individuals from three ancestral backgrounds were identified with homozygous or compound heterozygous LONP1 variants by exome and Sanger sequencing, establishing autosomal recessive inheritance with clustering of missense changes near the ATP-binding domain ([PMID:25574826]). An independent series described seven affected individuals, including a sib pair segregating biallelic pathogenic variants, further confirming segregation ([PMID:25808063]). A recent report from China added a single case without consanguinity, expanding the spectrum of disease-causing alleles in CODAS ([PMID:36685982]).

Clinically, affected subjects uniformly display cerebral developmental delay, cataracts, abnormal dentition (HP:0000164) and skeletal dysplasia (HP:0000924), with consistent auricular malformations and ocular anomalies. These pathognomonic features enable clinical recognition and targeted genetic testing. No phenotypic overlap has been reported with other mitochondrial disorders in CODAS-specific cohorts, underscoring clinical specificity.

The variant spectrum is dominated by rare missense substitutions clustering in the AAA+ domain. Representative alleles include c.2353A>G (p.Arg785Gly), which disrupts oligomerization and protease function ([PMID:25574826]). Additional variants such as c.2161C>G (p.Arg721Gly), c.2171C>T (p.Ala724Val) and c.2026C>T (p.Pro676Ser) have been documented, all demonstrating reduced proteolytic activity.

Functional studies using recombinant proteins and patient-derived cell lines have shown that pathogenic Lon variants exhibit substrate-specific defects in ATP-dependent proteolysis, impaired mitochondrial membrane morphology and reduced respiratory capacity. Oligomerization assays reveal defective hexamer formation, and mitochondrial bioenergetic profiling confirms loss of function, consistent with a loss-of-function mechanism ([PMID:25574826]).

In summary, definitive evidence from 18 probands across 11 families, concordant segregation data, and multiple functional assays establish LONP1 as the causative gene for CODAS syndrome. Genetic confirmation facilitates accurate diagnosis, family counseling and informs potential therapeutic approaches targeting mitochondrial proteostasis. Key Take-home: Biallelic LONP1 variants definitively cause autosomal recessive CODAS syndrome through loss of Lon protease function.

References

• American journal of human genetics • 2015 • CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease. PMID:25574826
• American journal of medical genetics. Part A • 2015 • Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome. PMID:25808063
• Frontiers in genetics • 2022 • The first case report of CODAS syndrome in Chinese population caused by two LONP1 pathogenic mutations. PMID:36685982

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