A Novel SLC25A4 Variant Causing Mitochondrial Dysfunction, Myopathy and Cardiomyopathy: A Functional and Molecular...

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Solute carrier family 25 member 4 (SLC25A4) gene variants are linked to various mitochondrial disorders.
• These disorders present with diverse clinical manifestations and inheritance patterns.

Purpose of the Study:

• To identify and characterize the disease-causing mutation in a Saudi family with a patient presenting myopathy and cardiomyopathy.
• To investigate the molecular and functional consequences of the identified SLC25A4 variant.

Main Methods:

• Whole exome sequencing and Sanger sequencing for genetic analysis.
• RT-PCR and quantitative RT-PCR to assess transcript-level effects.
• Seahorse assays to evaluate cellular respiration.

Main Results:

• A novel SLC25A4 variant (c.112-1G>C) was identified as the likely cause of disease.
• The variant results in aberrant splicing, a 6 bp in-frame deletion in ANT1 protein, and reduced SLC25A4 transcript levels.
• Patient-derived cells showed reduced oxygen consumption and extracellular acidification rates, indicating impaired mitochondrial function.

Conclusions:

• The findings expand the known spectrum of SLC25A4-associated mitochondrial diseases.
• The study highlights the importance of genetic analysis for diagnosing and understanding mitochondrial disorders.
• Results may guide genetic interventions like preimplantation genetic diagnosis and cascade testing.