Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency
| Autor: | James Davison, van, der, Westhuizen, Fh, Evangeline Wassmer, Langping He, Hue-Tran Hornig-Do, Francesca Meloni, Paul Gissen, Andrew C. Peet, Charlotte L. Alston, Iliana Ferrero, Paola Goffrini, Robert W. Taylor, Robert McFarland |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Mitochondrial Diseases SDHB Blotting Western Molecular Sequence Data SDHA Genetic screening/counselling Genes Recessive Saccharomyces cerevisiae Gene mutation Biology Electron Transport 03 medical and health sciences 0302 clinical medicine Germline mutation Paraganglioma Leukoencephalopathies Genetics medicine Humans Amino Acid Sequence Muscle Skeletal Genetics (clinical) Germ-Line Mutation 030304 developmental biology 0303 health sciences Base Sequence Electron Transport Complex II Leukodystrophy Genotype-Phenotype Correlations Genetic Complementation Test Infant Newborn Brain Infant medicine.disease Magnetic Resonance Imaging Mitochondrial disease 3. Good health Succinate Dehydrogenase Mitochondrial respiratory chain Neurology Child Preschool Mutation Female SDHD 030217 neurology & neurosurgery Metabolism Inborn Errors |
| Zdroj: | Journal of Medical Genetics |
| ISSN: | 1468-6244 0022-2593 |
| Popis: | Background Isolated complex II deficiency is a rare form of mitochondrial disease, accounting for approximately 2% of all respiratory chain deficiency diagnoses. The succinate dehydrogenase (SDH) genes (SDHA, SDHB, SDHC and SDHD) are autosomally-encoded and transcribe the conjugated heterotetramers of complex II via the action of two known assembly factors (SDHAF1 and SDHAF2). Only a handful of reports describe inherited SDH gene defects as a cause of paediatric mitochondrial disease, involving either SDHA (Leigh syndrome, cardiomyopathy) or SDHAF1 (infantile leukoencephalopathy). However, all four SDH genes, together with SDHAF2, have known tumour suppressor functions, with numerous germline and somatic mutations reported in association with hereditary cancer syndromes, including paraganglioma and pheochromocytoma. Methods and results Here, we report the clinical and molecular investigations of two patients with histochemical and biochemical evidence of a severe, isolated complex II deficiency due to novel SDH gene mutations; the first patient presented with cardiomyopathy and leukodystrophy due to compound heterozygous p.Thr508Ile and p.Ser509Leu SDHA mutations, while the second patient presented with hypotonia and leukodystrophy with elevated brain succinate demonstrated by MR spectroscopy due to a novel, homozygous p.Asp48Val SDHB mutation. Western blotting and BN-PAGE studies confirmed decreased steady-state levels of the relevant SDH subunits and impairment of complex II assembly. Evidence from yeast complementation studies provided additional support for pathogenicity of the SDHB mutation. Conclusions Our report represents the first example of SDHB mutation as a cause of inherited mitochondrial respiratory chain disease and extends the SDHA mutation spectrum in patients with isolated complex II deficiency. |
| Databáze: | OpenAIRE |
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