A novel MMUT splicing variant causing mild methylmalonic acidemia phenotype

Area of Science:

• Genetics
• Biochemistry
• Molecular Biology

Background:

• Methylmalonic acidemia (MMA) is a rare genetic disorder.
• Isolated MMA results from mutations in the methyl-malonyl coenzyme A mutase (MMUT) gene.
• Understanding genotype-phenotype correlations is crucial for MMA diagnosis.

Purpose of the Study:

• Investigate the molecular mechanisms of isolated MMA in a patient.
• Identify and characterize variants in the MMUT gene.
• Explore the impact of identified variants on MMUT gene splicing and protein production.

Main Methods:

• PCR amplification and Sanger sequencing of the MMUT gene.
• Minigene constructs to assess splicing defects.
• RT-PCR to analyze transcript levels.

Main Results:

• A compound heterozygous patient with isolated MMA was identified.
• The patient carried a known missense variant and a novel splice site variant (c.2125-2A>G) in the MMUT gene.
• The novel variant partially disrupted splicing, leading to reduced full-length MMUT transcript levels.

Conclusions:

• A novel splice site variant in MMUT contributes to isolated MMA.
• Reduced production of functional MMUT protein explains the mild phenotype.
• Molecular analysis and functional studies are vital for MMA diagnosis and understanding genotype-phenotype associations.