ME2 Deficiency Is Associated With Recessive Neurodevelopmental Disorder

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Malate is a key dicarboxylic acid in the tricarboxylic acid cycle.
• Deficiencies in fumarate hydrolase (FH) and malate dehydrogenase (MDH) are linked to recessive neurodevelopmental disorders (NDDs).
• Malic enzyme isoforms (ME1 and ME2) convert malate to pyruvate, but their role in Mendelian disease was unknown.

Purpose of the Study:

• To investigate the genetic basis of a patient presenting with NDD and other symptoms.
• To explore the role of malic enzyme 2 (ME2) in human health and disease.
• To identify novel genetic causes of Mendelian neurodevelopmental disorders.

Main Methods:

• Whole exome sequencing (WES) was performed on a patient with NDD.
• A homozygous frameshift variant in the ME2 gene was identified.
• Functional studies involving yeast ortholog deletion and complementation were conducted.

Main Results:

• A novel homozygous frameshift variant (c.1379_1380delTT, p.Phe460fs*22) in the ME2 gene was found in the patient.
• The identified variant resulted in a truncated and unstable ME2 protein.
• Deletion of the yeast ortholog of ME2 caused growth arrest, rescued by ME2 re-expression, confirming ME2's essential role.

Conclusions:

• This study reports the first Mendelian human disease caused by a biallelic variant in a malic enzyme gene, specifically ME2.
• The findings support ME2 deficiency as a cause of recessive NDD.
• Further research is needed to fully characterize ME2-associated recessive NDD.