Recessive pathogenic variants in MCAT cause combined oxidative phosphorylation deficiency

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Malonyl-CoA-acyl carrier protein transacylase (MCAT) is essential for mitochondrial fatty acid synthesis (mtFAS).
• Previous studies linked mtFAS gene dysfunction, including MCAT, to reduced electron transport chain (ETC) complexes in mouse models.
• Mitochondrial dysfunction is implicated in various human diseases.

Purpose of the Study:

• To investigate the clinical and molecular basis of a patient with unexplained hypotonia and developmental delay.
• To identify the genetic cause of observed mitochondrial dysfunction.
• To establish a link between MCAT dysfunction and human disease.

Main Methods:

• Whole exome sequencing was performed on a proband with severe clinical symptoms.
• Biochemical assays were used to measure ETC enzyme activities and protein levels (NDUFB8, COXII, SDHB) in patient-derived cells (lymphoblasts and fibroblasts).
• Functional rescue experiments were conducted by re-expressing wild-type MCAT in patient fibroblasts.

Main Results:

• Biallelic pathogenic variants in the MCAT gene were identified in the proband.
• Patient cells showed significantly reduced levels of ETC complex subunits and decreased ETC enzyme activities.
• Re-expression of wild-type MCAT restored normal cellular function in patient fibroblasts, confirming pathogenicity.

Conclusions:

• This study reports the first human patient with pathogenic MCAT variants.
• MCAT deficiency leads to combined oxidative phosphorylation deficiency and severe clinical phenotypes.
• MCAT is critical for maintaining mitochondrial function and overall health.