DNM1 – Lennox-Gastaut Syndrome

Dynamin-1, encoded by DNM1, is a neuron-specific GTPase essential for synaptic vesicle endocytosis. Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic encephalopathy characterized by multiple seizure types, intellectual disability, and a characteristic EEG pattern (Lennox-Gastaut syndrome).

DNM1-related encephalopathy follows an autosomal dominant inheritance with de novo heterozygous variants. No familial segregation has been reported beyond mosaic parental transmission, indicating sporadic occurrence.

Multiple independent de novo missense variants in DNM1 have been identified in individuals with LGS. A novel c.127G>A (p.Gly43Ser) was found in one LGS patient ([PMID:26611353]) and the recurrent c.709C>T (p.Arg237Trp) variant was observed in seven patients, several of whom developed LGS following infantile spasms ([PMID:28667181]). Additional de novo variants cluster in the GTPase and middle domains and expand the phenotypic spectrum to include LGS.

The DNM1 variant spectrum in LGS is dominated by missense changes: c.127G>A (p.Gly43Ser), c.709C>T (p.Arg237Trp), c.618G>T (p.Lys206Asn), c.529G>C (p.Ala177Pro), and c.1076G>C (p.Gly359Ala), all acting via a dominant-negative mechanism. These variants impair GTP binding, oligomerization, and vesicle fission without evidence of haploinsufficiency.

Functional assays corroborate the genetic findings: mutant DNM1 constructs reduce synaptic vesicle endocytosis in HeLa and neuronal cells, disrupt higher-order oligomerization, and recapitulate seizure phenotypes in mouse models (fitful and R237W) ([PMID:27066543], [PMID:20700442], [PMID:27363778]). Rescue experiments with splice-variant-specific models highlight the dominant-negative action of exon 10a mutations.

Collectively, these data support a Strong gene–disease association. De novo DNM1 mutations cause LGS through a dominant-negative mechanism, providing a basis for genetic diagnosis and potential targeted therapies. Key Take-home: DNM1 should be included in clinical genetic testing for LGS, and its dominant-negative variants offer targets for therapeutic intervention.

References

• Epilepsia • 2016 • De novo DNM1 mutations in two cases of epileptic encephalopathy. PMID:26611353
• Neurology • 2017 • DNM1 encephalopathy: A new disease of vesicle fission. PMID:28667181
• Neurology. Genetics • 2015 • Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. PMID:27066543
• PLoS genetics • 2010 • A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. PMID:20700442
• Neurobiology of disease • 2016 • Dynamin 1 isoform roles in a mouse model of severe childhood epileptic encephalopathy. PMID:27363778

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