Biallelic Mutations in DNM1L are Associated with a Slowly Progressive Infantile Encephalopathy
Alessia Nasca1, Andrea Legati1, Enrico Baruffini2
1Unit of Molecular Neurogenetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
Abstract:
Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion, and mitochondrial dynamics is important for several cellular functions. DNM1L is the most important mediator of mitochondrial fission, with a role also in peroxisome division. Few reports of patients with genetic defects in DNM1L have been published, most of them describing de novo dominant mutations. We identified compound heterozygous DNM1L variants in two brothers presenting with an infantile slowly progressive neurological impairment. One variant was a frame-shift mutation, the other was a missense change, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. In conclusion, we described a recessive disease caused by DNM1L mutations, with a clinical phenotype resembling mitochondrial disorders but without any biochemical features typical of these syndromes (lactic acidosis, respiratory chain complex deficiency) or indicating a peroxisomal disorder.
Insights
Genetic defects in DNM1L cause a rare, recessive neurological disorder. This study identifies compound heterozygous variants in DNM1L, leading to impaired mitochondrial and peroxisome fission in affected individuals.
Area of Science:
- Cell Biology
- Genetics
- Neuroscience
Background:
- Mitochondrial dynamics, involving fission and fusion, are crucial for cellular functions.
- DNM1L is a key mediator of mitochondrial fission and also involved in peroxisome division.
- Previous reports of DNM1L genetic defects primarily described de novo dominant mutations.
Purpose of the Study:
- To investigate the genetic basis of a rare infantile neurological impairment.
- To characterize the cellular consequences of novel DNM1L variants.
- To establish a recessive inheritance pattern for DNM1L-associated disease.
Main Methods:
- Genetic analysis to identify variants in two affected brothers.
- Functional validation of a missense variant using a yeast model.
- Fluorescence microscopy of patient-derived fibroblasts to assess mitochondrial and peroxisome morphology.
Main Results:
- Identified compound heterozygous DNM1L variants (one frameshift, one missense) in the affected siblings.
- Demonstrated impaired mitochondrial and peroxisome fission in fibroblasts from the patients.
- Observed abnormally elongated mitochondria and aberrant peroxisomes, indicating defective fission.
Conclusions:
- Described a novel recessive disorder caused by DNM1L mutations.
- The clinical phenotype mimics mitochondrial disorders but lacks typical biochemical markers.
- This study expands the known spectrum of DNM1L-related diseases and their inheritance patterns.
