Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease

Area of Science:

• Genetics
• Molecular Biology
• Mitochondrial Biology

Background:

• Mitochondrial dysfunction underlies numerous human disorders.
• Mendelian genetic disorders affecting mitochondrial RNA biology are increasingly recognized.
• The PDE12 gene is crucial for mitochondrial non-coding RNA quality control.

Purpose of the Study:

• To investigate the role of PDE12 variants in mitochondrial disorders.
• To identify the genetic basis of neurological and muscular phenotypes associated with mitochondrial dysfunction.

Main Methods:

• Whole exome sequencing in affected individuals.
• Analysis of patient-derived primary fibroblasts.
• Mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq).

Main Results:

• Novel, segregating bi-allelic PDE12 missense variants were identified in three families.
• Patients exhibited in utero and neonatal onset, muscle and brain involvement, cytochrome c oxidase deficiency, and lactic acidosis.
• Fibroblasts showed reduced PDE12 protein and accumulation of aberrant mitochondrial RNAs.

Conclusions:

• PDE12 variants cause mitochondrial respiratory chain deficiencies.
• Loss of PDE12 function disrupts mitochondrial RNA processing, leading to neurological and muscular phenotypes.
• PDE12 is essential for maintaining mitochondrial function and preventing disease.