Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired
Ruth Sheffer1,2, Liza Douiev1,2, Simon Edvardson1
1Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Abstract:
An emerging class of mitochondrial disorders is caused by mutations in nuclear genes affecting mitochondrial dynamics and function. One of these is the DNM1L gene encoding the dynamin-related protein 1 (DRP1), which is pivotal in the mitochondrial fission process. Here, we describe a patient with a novel dominant-negative, de novo DNM1L mutation, which expands the clinical spectrum. The patient reported here exhibits a chronic neurological disorder, characterized by postnatal microcephaly, developmental delay, and pain insensitivity. Muscle biopsy disclosed decreased respiratory chain complex IV activity. Exome sequencing showed a de novo heterozygous c.1084G>A (p.G362S) mutation. Subsequent studies of patient skin fibroblasts showed markedly impaired mitochondrial fission and a partial respiratory chain defect while peroxisomal morphology remained intact. Human foreskin fibroblasts over-expressing the mutant DNM1L gene displayed aberrant mitochondrial morphology. © 2016 Wiley Periodicals, Inc.
Insights
A novel mutation in the DNM1L gene causes a severe neurological disorder affecting mitochondrial dynamics. This discovery expands the understanding of mitochondrial fission defects and related diseases.
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Neuroscience
Background:
- Mitochondrial disorders can arise from nuclear gene mutations impacting mitochondrial dynamics.
- The DNM1L gene, encoding dynamin-related protein 1 (DRP1), is crucial for mitochondrial fission.
Observation:
- A patient presented with a chronic neurological disorder including microcephaly, developmental delay, and pain insensitivity.
- Muscle biopsy revealed reduced respiratory chain complex IV activity.
- Exome sequencing identified a de novo heterozygous DNM1L mutation (c.1084G>A, p.G362S).
Findings:
- Patient fibroblasts exhibited impaired mitochondrial fission and a partial respiratory chain defect.
- Peroxisomal morphology was unaffected.
- Overexpression of the mutant DNM1L gene in fibroblasts led to abnormal mitochondrial morphology.
Implications:
- This novel DNM1L mutation expands the clinical spectrum of mitochondrial dynamics disorders.
- Understanding DRP1 function is key to diagnosing and potentially treating these complex neurological conditions.
- The findings highlight the critical role of mitochondrial fission in human health and disease.
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