DNM1 – Developmental and Epileptic Encephalopathy

Heterozygous pathogenic variants in DNM1 cause an autosomal dominant form of developmental and epileptic encephalopathy (DEE), presenting with infantile spasms, refractory seizures, severe to profound intellectual disability, hypotonia, and global developmental delay. To date, over 50 unrelated individuals with de novo DNM1 variants have been reported ([PMID:28667181]).

Most pathogenic DNM1 alleles are de novo missense or splice-site variants clustering in the GTPase and middle domains. A recurrent hotspot c.709C>T (p.Arg237Trp) accounts for approximately one-third of cases ([PMID:28667181]). Eleven individuals harbor the recurrent c.1197-8G>A splice variant affecting exon 10a, which acts through a dominant-negative mechanism ([PMID:36413998]). Other missense variants such as p.Ala177Pro and p.Lys206Asn have been shown to disrupt oligomerization-dependent GTPase activity ([PMID:27066543]).

Autosomal recessive DEE due to homozygous loss-of-function variants has been described in consanguineous families. Case reports include c.350del (p.Pro117fs) and p.Gln33Ter, which segregate fully in affected individuals, with heterozygous carriers remaining asymptomatic ([PMID:36553519]; [PMID:34172529]).

Segregation analysis in recessive pedigrees confirms complete cosegregation of biallelic variants with disease, and a mosaic parent transmitted a dominant-negative allele to two affected siblings ([PMID:28667181]). Overall, one additional affected relative has been documented in a familial context.

Functional studies across cellular and animal models demonstrate that dominant-negative DNM1 variants impair synaptic vesicle endocytosis and vesicle scission. Transferrin uptake assays and electron microscopy in mutant-expressing cells show vesicle budding defects, and a knock-in mouse model carrying p.Arg237Trp exhibits seizures and synaptic dysfunction that are rescued by the small molecule BMS-204352 ([PMID:27066543]; [PMID:37648685]).

No conflicting evidence has been reported to dispute the association. The concordant genetic and functional data support loss of GTPase-dependent vesicle fission as the pathogenic mechanism in DNM1-related DEE.

Key Take-home: DNM1 pathogenic variants are definitively associated with developmental and epileptic encephalopathy, and genetic testing for de novo missense/splice and recessive truncating alleles guides diagnosis and therapeutic research into synaptic vesicle recycling.

References

• Neurology • 2017 • DNM1 encephalopathy: A new disease of vesicle fission. PMID:28667181
• American journal of human genetics • 2022 • A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism. PMID:36413998
• Neurology. Genetics • 2015 • Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis. PMID:27066543
• Nature communications • 2023 • Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy. PMID:37648685
• Genes • 2022 • Clinical, Radiological, and Genetic Characterization of a Patient with a Novel Homoallelic Loss-of-Function Variant in DNM1. PMID:36553519
• Journal of medical genetics • 2022 • Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state. PMID:34172529

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