The phenotypic spectrum of PTCD3 deficiency

Area of Science:

• Genetics and Molecular Biology
• Mitochondrial Biology
• Neurogenetics

Background:

• The PTCD3 gene encodes a protein crucial for mitochondrial small ribosomal subunit function and mRNA binding.
• Pathogenic variants in PTCD3 are associated with mitochondrial disorders, but clinical manifestations require further elucidation.
• Mitochondrial dysfunction underlies various severe early-onset neurological conditions.

Purpose of the Study:

• To expand the clinical spectrum of PTCD3 pathogenic variants.
• To characterize novel PTCD3 variants and their impact on mitochondrial function.
• To investigate genotype-phenotype correlations in patients with PTCD3-related disorders.

Main Methods:

• Whole genome and whole exome sequencing to identify PTCD3 variants.
• Clinical assessment of patients, including neurological examination and neuroimaging (MRI).
• Biochemical assays measuring basal respiration rates.
• In silico modeling and RT-PCR to assess variant effects on protein structure and splicing.

Main Results:

• Two novel heterozygous PTCD3 variants (c.1182T>A, p.(Tyr394Ter) and c.805C>T, p.(His269Tyr)) were identified in siblings with Leigh-like syndrome, characterized by ataxia, nystagmus, and reduced basal respiration.
• The Tyr394Ter variant disrupts the protein's C-terminal domain, while His269Tyr shows minimal structural impact in silico.
• A third patient presented with global developmental delay and hypotonia, associated with the PTCD3 splice variant c.538+4A>G, which causes exon skipping.

Conclusions:

• PTCD3 pathogenic variants contribute to a spectrum of mitochondrial disorders, ranging from severe early-onset Leigh-like syndrome to milder neurodegenerative phenotypes.
• These findings highlight the critical role of PTCD3 in mitochondrial protein synthesis and overall cellular respiration.
• Further research into PTCD3 variants is essential for understanding mitochondrial disease pathogenesis and developing therapeutic strategies.