YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria.

Area of Science:

• Biochemistry
• Genetics
• Mitochondrial Biology

Background:

• 3-methylglutaconic aciduria (3-MGCA) is a biochemical marker for inherited metabolic disorders, categorized as primary or secondary.
• Secondary 3-MGCA involves impaired mitochondrial energy metabolism.
• The genetic basis for many secondary 3-MGCA conditions remains largely unknown.

Purpose of the Study:

• To identify the genetic cause of 3-MGCA in siblings with sensorineural hearing loss and neurological issues.
• To characterize the functional consequences of a novel YME1L1 gene variant.
• To classify this newly identified condition within the spectrum of 3-MGCA disorders.

Main Methods:

• Whole-exome sequencing to identify genetic variants.
• Functional assays to assess YME1L1 protease activity on substrates like OPA1 and PRELID1.
• Analysis of mitochondrial morphology (fission/fusion) in patient-derived fibroblasts.
• Assessment of Krebs cycle enzyme activity and mitochondrial respiration.

Main Results:

• A novel homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene was identified in affected siblings.
• The YME1L1 variant impairs proteolytic processing of mitochondrial proteins, leading to mitochondrial fragmentation.
• Patient cells exhibit reduced mitochondrial respiration and attenuated Krebs cycle enzyme activity.
• This dysfunction explains the accumulation of 3-methylglutaconic and 3-methylglutaric acids.

Conclusions:

• YME1L1 deficiency is identified as a novel cause of secondary 3-MGCA.
• This finding expands the known genetic causes of 3-MGCA.
• The study facilitates improved diagnosis of inherited metabolic disorders presenting with 3-MGCA.