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Published on: August 15, 2019
Biallelic variants in SUPV3L1 cause a variable leukodystrophy due to impaired mitochondrial degradosome function
Lydia Green1,2, Noémie Hamilton3,4, Marilena Elpidorou1
1Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
Research Square
|July 17, 2026
Summary
Mutations in SUPV3L1 cause a spectrum of neurodevelopmental disorders, including encephalopathy and motor deficits. This dysfunction activates type 1 interferon signaling, potentially through microglia.
Area of Science:
- Cellular Biology
- Neuroscience
- Immunology
Background:
- Double-stranded RNA (dsRNA) sensing is critical for cellular defense.
- Mitochondrial dsRNA degradation involves PNPT1 and SUPV3L1.
- Biallelic PNPT1 mutations cause early-onset encephalopathy.
Purpose of the Study:
- To define the clinical and radiological impact of SUPV3L1 dysfunction.
- To investigate the role of SUPV3L1 in human disease.
Main Methods:
- International collaboration identified 21 patients with biallelic SUPV3L1 mutations.
- Clinical and radiological data were analyzed.
- A SUPV3L1 knock-out zebrafish model was generated.
Main Results:
- Fifteen distinct biallelic SUPV3L1 variants were found in 21 individuals.
- Clinical spectrum includes neonatal hematological issues, motor disorders, and acute encephalopathy.
- Neurodevelopmental involvement (motor delay, intellectual impairment), microcephaly, and spasticity were common.
- Increased interferon signature observed in patients and zebrafish models.
- Zebrafish showed mitochondrial and microglial defects.
Conclusions:
- The genetic, clinical, and radiological spectrum of SUPV3L1-associated disease is defined.
- Dysplastic microglia-mediated type 1 interferon pathway activation is a potential cause.
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