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SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy
Daniele Ghezzi1, Paola Goffrini, Graziella Uziel
1Unit of Molecular Neurogenetics-Pierfranco and Luisa Mariani Center for Study of Children's Mitochondrial Disorders, Foundation IRCCS Neurological Institute C. Besta, Milan, Italy.
Nature Genetics
|May 26, 2009
Summary
Mutations in SDHAF1 cause infantile leukoencephalopathy by disrupting succinate dehydrogenase (complex II) assembly. Restoring wild-type SDHAF1 in cells can fix this defect, highlighting its role as an essential assembly factor.
Area of Science:
- Biochemistry
- Genetics
- Cell Biology
Background:
- Infantile leukoencephalopathy is a severe neurological disorder.
- Defects in the mitochondrial electron transport chain, specifically succinate dehydrogenase (SDH, complex II), are implicated in various diseases.
- The assembly factors for SDH are not well understood.
Purpose of the Study:
- To identify the genetic cause of infantile leukoencephalopathy with defective SDH.
- To investigate the function of the identified gene, SDHAF1, in SDH assembly and cellular respiration.
- To establish SDHAF1 as a potential therapeutic target.
Main Methods:
- Genetic analysis of patients with infantile leukoencephalopathy.
- Functional studies in yeast to assess the impact of gene disruption on SDH activity.
- Cellular assays using patient-derived fibroblasts to evaluate SDH function and gene rescue.
Main Results:
- Mutations in SDHAF1 were identified as causative for infantile leukoencephalopathy.
- Disruption of the yeast homolog of SDHAF1 led to SDH deficiency and impaired oxidative phosphorylation (OXPHOS).
- Re-expression of wild-type SDHAF1 in patient fibroblasts restored SDH activity and amount.
Conclusions:
- SDHAF1 is a crucial assembly factor for succinate dehydrogenase (complex II).
- SDHAF1 mutations lead to mitochondrial dysfunction and infantile leukoencephalopathy.
- SDHAF1 represents the first identified bona fide SDH assembly factor in any organism.
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