3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C>G, p.Leu667Val) in the YME1L1 gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.

• Klíčová slova
• 3‐methylglutaconic aciduria, YME1L1, inherited metabolic disorders, mitochondrial disorders, mitochondrial dysfunction, mitochondrial fragmentation,
• MeSH
• dítě MeSH
• fibroblasty metabolismus   MeSH
• glutaráty MeSH
• lidé MeSH
• metaloendopeptidasy * genetika   metabolismus   MeSH
• missense mutace MeSH
• mitochondriální dynamika MeSH
• mitochondriální proteiny * genetika   MeSH
• mitochondrie metabolismus   MeSH
• percepční nedoslýchavost genetika   MeSH
• sourozenci MeSH
• vrozené poruchy metabolismu * genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• 3-methylglutaconic acid MeSH Prohlížeč
• glutaráty MeSH
• metaloendopeptidasy * MeSH
• mitochondriální proteiny * MeSH