DNM1L – Autosomal Dominant Optic Atrophy, Classic Form

Autosomal dominant optic atrophy (ADOA) is a progressive neuro-ophthalmological disorder characterized by degeneration of retinal ganglion cells and optic nerve atrophy. Most ADOA cases are due to mutations in OPA1, with rarer forms involving OPA3, MFN2, AFG3L2 and SPG7. Recent exome sequencing expanded the genetic landscape by implicating DNM1L in classic ADOA (MONDO:0008134).

In a cohort of three large pedigrees, heterozygous missense variants in DNM1L segregated with isolated optic atrophy under an autosomal dominant inheritance model (3 families) (PMID:28969390). Two distinct DNM1L variants, c.614C>A (p.Ala205Glu) and c.5A>C (p.Glu2Ala), were identified in affected individuals from unrelated families, each showing full penetrance and cosegregation with disease. No unaffected carriers were observed in these lineages, supporting pathogenicity of the variants.

DNM1L encodes dynamin-related protein 1 (DRP1), a large GTPase essential for mitochondrial fission and network dynamics. The p.Ala205Glu and p.Glu2Ala substitutions map to the GTPase domain, likely perturbing GTP hydrolysis and oligomerization required for membrane constriction. These dominant variants are predicted to exert a dominant-negative effect by interfering with wild-type DRP1 assembly at scission sites.

Functional analyses in patient-derived fibroblasts revealed normal expression levels of mutant DNM1L but aberrant homo-polymerization forming cytoplasmic aggregates on highly tubulated mitochondrial networks, with no changes in peroxisomal structure or respiratory complexes (PMID:28969390). In vivo, Dnm1l⁺/⁻ mice recapitulated key features, showing increased mitochondrial length in retinal ganglion cell somata and axons without overt neurodegeneration, illustrating a conserved impact on mitochondrial dynamics in optic neurons.

No conflicting reports have challenged the DNM1L–ADOA link, and experimental and genetic data are concordant. Together, these findings fulfill ClinGen criteria for a strong gene–disease association, supporting the inclusion of DNM1L in clinical genetic testing for ADOA. Key take-home: Dominant DNM1L variants disrupt mitochondrial fission in retinal ganglion cells and represent a validated cause of classic autosomal dominant optic atrophy.

References

• Brain • 2017 • Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. PMID:28969390

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