Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency
Charlotte L Alston1, James E Davison, Francesca Meloni
1Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, UK.
Journal of Medical Genetics
|September 14, 2012
Summary
This study identifies novel mutations in SDH genes causing severe isolated complex II deficiency, a rare mitochondrial disease. It highlights new genetic causes for Leigh syndrome and expands the known spectrum of SDHA and SDHB mutations.
Area of Science:
- Biochemistry
- Genetics
- Mitochondrial Biology
Background:
- Isolated complex II deficiency is a rare mitochondrial disease (2% of diagnoses).
- Succinate dehydrogenase (SDH) genes (SDHA-D) encode complex II subunits, with assembly factors SDHAF1 and SDHAF2 involved.
- SDH genes and SDHAF2 have tumor suppressor roles, linked to hereditary cancers.
Purpose of the Study:
- To investigate the clinical and molecular basis of severe isolated complex II deficiency in two pediatric patients.
- To identify novel mutations in SDH genes causing mitochondrial disease.
- To expand the understanding of SDHA and SDHB gene mutations in inherited respiratory chain disorders.
Main Methods:
- Clinical and molecular investigations of two patients.
- Histochemical and biochemical analyses for complex II deficiency.
- Western blotting, BN-PAGE, and yeast complementation studies.
- MR spectroscopy for brain succinate levels.
Main Results:
- Patient 1: Compound heterozygous SDHA mutations (p.Thr508Ile, p.Ser509Leu) causing cardiomyopathy and leukodystrophy.
- Patient 2: Homozygous SDHB mutation (p.Asp48Val) causing hypotonia, leukodystrophy, and elevated brain succinate.
- Biochemical studies confirmed decreased SDH subunits and impaired complex II assembly.
- Yeast complementation supported SDHB mutation pathogenicity.
Conclusions:
- This is the first report of an SDHB mutation causing inherited mitochondrial respiratory chain disease.
- The study expands the known mutation spectrum for SDHA in isolated complex II deficiency.
- Novel SDH gene mutations are significant causes of severe pediatric mitochondrial disease.
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