DNM1L – Encephalopathy due to mitochondrial and peroxisomal fission defect

DNM1L encodes dynamin-related protein 1 (DRP1), a GTPase critical for mitochondrial and peroxisomal division DNM1L. Heterozygous de novo missense variants in DNM1L cause an early-onset encephalopathy marked by global developmental delay, refractory epilepsy, and hyperfused mitochondrial networks. The phenotype was first reported in a neonate with lethal encephalopathy and subsequently identified in a second individual with prolonged survival and nonspecific EEG findings (PMID:26604000). Two additional unrelated cases harboring the recurrent c.1246C>T (p.Arg416Cys) variant expand the spectrum to late-childhood focal status epilepticus (PMID:27145208).

Pathogenic alleles are exclusively missense changes clustering in the middle (oligomerization) domain. To date, five unique de novo variants (e.g., c.1085G>A (p.Gly362Asp), c.1246C>T (p.Arg416Cys)) have been reported in four unrelated probands, with no evidence of transmission (PMID:26604000; PMID:27145208). The absence of loss-of-function alleles and recurrence of specific residues support a dominant-negative mechanism.

Patient-derived fibroblasts exhibit striking mitochondrial hyperfusion and subtle cristae disorganization despite normal respiratory chain parameters (PMID:26604000). In yeast, equivalent VPS1 mutations produce dominant-negative vacuolar protein sorting defects and impaired oligomerization (PMID:9372190). In Drosophila, human middle-domain DNM1L variants fail to rescue drp1-null lethality and induce peroxisomal and mitochondrial hyperfusion in multiple tissues (PMID:26931468).

Mechanistically, middle domain variants impede DRP1 oligomerization and assembly-stimulated GTP hydrolysis without preventing mitochondrial recruitment, thereby blocking membrane scission and causing organelle hyperfusion. Biophysical characterization of P-loop and stalk mutants confirms stable nucleotide binding but defective conformational transitions required for fission.

The cumulative data meet ClinGen Moderate clinical validity criteria for the DNM1L–encephalopathy due to mitochondrial and peroxisomal fission defect association. Diagnostic DNM1L sequencing is warranted in patients with unexplained developmental delay and refractory epilepsy, particularly when mitochondrial hyperfusion is observed. Key Take-home: De novo DNM1L middle-domain missense variants act dominantly to impair mitochondrial fission, presenting as a refractory epileptic encephalopathy.

References

• European journal of human genetics : EJHG • 2016 • DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. PMID:26604000
• American journal of medical genetics. Part A • 2016 • A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy. PMID:27145208
• Human molecular genetics • 2016 • Missense variants in the middle domain of DNM1L in cases of infantile encephalopathy alter peroxisomes and mitochondria when assayed in Drosophila. PMID:26931468
• Biological chemistry • 1997 • Cloning and characterization of a dominant-negative vps1 allele of the yeast Saccharomyces cerevisiae. PMID:9372190

Evidence Based Scoring (AI generated)