A DNM1L GTPase Effector Domain Deletion Causes Intermediate Defects in Peroxisomal and Mitochondrial Dynamics and Reveals a Targetable Metabolic Vulnerability
- 1Baylor College of Medicine
Abstract
DNM1L encodes dynamin-related protein 1 (DRP1), a key GTPase regulating mitochondrial and peroxisomal dynamics. Pathogenic DNM1L variants are associated with a broad spectrum of neurodevelopmental and neurodegenerative disorders, with phenotypic severity varying by affected protein domain. While variants in the GTPase domain are typically associated with milder phenotypes and middle-domain variants with severe developmental and epileptic encephalopathy, the functional impact of GTPase effector domain (GED) variants remains less defined. Here, we describe four individuals harboring a recurrent heterozygous GED deletion (L700del) presenting with movement disorders and lacking severe infantile encephalopathy, consistent with an intermediate clinical phenotype. Patient-derived fibroblasts exhibited tubular peroxisomes and enlarged mitochondria, while Drosophila models demonstrated that DNM1LL700del has intermediate functional effects that were more pronounced than those of a GTPase-domain variant A192E but less severe than those of the middle-domain variant G350R. Comparison with another GED variant, Y691C, further demonstrated variant-specific differences in severity within the GED. Metabolic stress assays showed that L700del fibroblasts exhibited impaired growth under galactose conditions, consistent with increased vulnerability under conditions dependent on mitochondrial oxidative metabolism. Bezafibrate, a PPAR agonist that promotes mitochondrial biogenesis, partially rescued this growth defect. Together, these findings support a functional allelic spectrum in DNM1L-associated disease in which protein domain contributes to, but does not completely determine, functional severity. L700del represents an intermediate-strength allele associated with a movement-disorder phenotype and a pharmacologically modifiable metabolic vulnerability.
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BibTeX
@misc{srivastav2026dnm1l,
title = {{A DNM1L GTPase Effector Domain Deletion Causes Intermediate Defects in Peroxisomal and Mitochondrial Dynamics and Reveals a Targetable Metabolic Vulnerability}},
author = {S. Srivastav and S. Jangam and J. Andrews and E. Theodorou and L. C. Briere and G. D. Quintana and I. L. Gomes and J. A. Saute and P. Bhagwat and A. Subramaniam and N. Roy and E. Macnamara and A. Sanchez-Valle and C. Gordillo and H. J. Bellen and S. Yamamoto and S. Lalani and F. A. High and M. A. Walker and L. Simao Medeiros and D. A. Sweetser and M. F. Wangler},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.763232},
url = {https://www.biorxiv.org/content/10.64898/2026.11.03.763232v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A DNM1L GTPase Effector Domain Deletion Causes Intermediate Defects in Peroxisomal and Mitochondrial Dynamics and Reveals a Targetable Metabolic Vulnerability
AU - S. Srivastav
AU - S. Jangam
AU - J. Andrews
AU - E. Theodorou
AU - L. C. Briere
AU - G. D. Quintana
AU - I. L. Gomes
AU - J. A. Saute
AU - P. Bhagwat
AU - A. Subramaniam
AU - N. Roy
AU - E. Macnamara
AU - A. Sanchez-Valle
AU - C. Gordillo
AU - H. J. Bellen
AU - S. Yamamoto
AU - S. Lalani
AU - F. A. High
AU - M. A. Walker
AU - L. Simao Medeiros
AU - D. A. Sweetser
AU - M. F. Wangler
PY - 2026
DA - 2026/11/03
PB - bioRxiv
DO - 10.64898/2026.11.03.763232
UR - https://www.biorxiv.org/content/10.64898/2026.11.03.763232v1
AB - DNM1L encodes dynamin-related protein 1 (DRP1), a key GTPase regulating mitochondrial and peroxisomal dynamics. Pathogenic DNM1L variants are associated with a broad spectrum of neurodevelopmental and neurodegenerative disorders, with phenotypic severity varying by affected protein domain. While variants in the GTPase domain are typically associated with milder phenotypes and middle-domain variants with severe developmental and epileptic encephalopathy, the functional impact of GTPase effector domain (GED) variants remains less defined. Here, we describe four individuals harboring a recurrent heterozygous GED deletion (L700del) presenting with movement disorders and lacking severe infantile encephalopathy, consistent with an intermediate clinical phenotype. Patient-derived fibroblasts exhibited tubular peroxisomes and enlarged mitochondria, while Drosophila models demonstrated that DNM1LL700del has intermediate functional effects that were more pronounced than those of a GTPase-domain variant A192E but less severe than those of the middle-domain variant G350R. Comparison with another GED variant, Y691C, further demonstrated variant-specific differences in severity within the GED. Metabolic stress assays showed that L700del fibroblasts exhibited impaired growth under galactose conditions, consistent with increased vulnerability under conditions dependent on mitochondrial oxidative metabolism. Bezafibrate, a PPAR agonist that promotes mitochondrial biogenesis, partially rescued this growth defect. Together, these findings support a functional allelic spectrum in DNM1L-associated disease in which protein domain contributes to, but does not completely determine, functional severity. L700del represents an intermediate-strength allele associated with a movement-disorder phenotype and a pharmacologically modifiable metabolic vulnerability.
ER -