A DNM1L GTPase Effector Domain Deletion Causes Intermediate Defects in Peroxisomal and Mitochondrial Dynamics and Reveals a Targetable Metabolic Vulnerability

A recurrent heterozygous DNM1L GED deletion, L700del, produces intermediate defects in peroxisomal and mitochondrial dynamics and links to galactose-dependent growth impairment in patient fibroblasts.

• Why it matters: Domain-specific DNM1L variant effects are clinically important, but the functional consequences of GTPase effector domain (GED) changes are less defined.
• What they did: Four individuals with L700del were studied using patient-derived fibroblasts, Drosophila models, and metabolic stress assays; L700del effects were compared with A192E, G350R, and Y691C.
• The result: L700del fibroblasts showed tubular peroxisomes and enlarged mitochondria, and exhibited impaired growth under galactose; bezafibrate partially rescued the defect, suggesting a targetable metabolic vulnerability.

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