Respiratory complex I deficiency caused by a novel multi-exonic PUS1 deletion

Area of Science:

• Genetics and Genomics
• Mitochondrial Biology
• Rare Diseases

Background:

• Myopathy, lactic acidosis, and sideroblastic anemia type 1 (MLASA1) is an extremely rare mitochondrial disorder.
• It is caused by pathogenic variants in the PUS1 gene, crucial for mitochondrial protein synthesis.

Purpose of the Study:

• To describe the genetic and phenotypic characteristics of MLASA1 in two affected siblings.
• To identify the underlying genetic cause of MLASA1 in these patients.
• To expand the understanding of PUS1-related disorders.

Main Methods:

• Whole-exome sequencing with depth-based copy number variation (CNV) analysis.
• Sanger sequencing to define deletion breakpoints.
• Skeletal muscle histology and immunohistochemistry.

Main Results:

• A novel homozygous multi-exonic deletion in PUS1 was identified in the affected siblings.
• The deletion resulted in the loss of the C-terminal coding region of PUS1.
• Skeletal muscle analysis revealed ragged red fibers and impaired respiratory chain complex I assembly due to loss of NDUFB8.

Conclusions:

• The findings expand the genotypic and phenotypic spectrum of MLASA1.
• CNV analysis is valuable for diagnosing unresolved mitochondrial disorders.
• Impairment of PUS1 affects translation-dependent respiratory chain components, particularly complex I.