ArticleBMC cancer2017
Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma.
Article in BMC cancer, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Differential expression of nuclear-derived mitochondrial succinate dehydrogenase genes in metabolically active buffalo tissues.Molecular biology reports · 2024Article
- Article
- Cardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy.Nature communications · 2022Article
- Somatic Mutation Profiling in Head and Neck Paragangliomas.The Journal of clinical endocrinology and metabolism · 2022Article
- Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain.International journal of molecular sciences · 2021Review
- Widespread polycistronic gene expression in green algae.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions.International journal of molecular sciences · 2021Review
- Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome.The Biochemical journal · 2020Review
- Mutation profiling in eight cases of vagal paragangliomas.BMC medical genomics · 2020Article
- MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression.PLoS genetics · 2020Article
- A Novel MAX Gene Mutation Variant in a Patient With Multiple and "Composite" Neuroendocrine-Neuroblastic Tumors.Frontiers in endocrinology · 2020Article
- A Mitochondrial LYR Protein Is Required for Complex I Assembly.Plant physiology · 2019Article
- Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction.Progress in biophysics and molecular biology · 2019Article
- The assembly of succinate dehydrogenase: a key enzyme in bioenergetics.Cellular and molecular life sciences : CMLS · 2019Review
- The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes.Endocrine pathology · 2019Review
- Assembly of mammalian oxidative phosphorylation complexes I-V and supercomplexes.Essays in biochemistry · 2018Review
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundGermline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL). As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH.
methodsDNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes. Molecular and functional consequences of an identified sequence variant of SDHAF3 were assessed in yeast and mammalian cells (HEK293).
resultsUsing massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063). In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells. We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3. As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction. Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant.
conclusionsOur studies reveal novel insights into the biogenesis of SDH, uncovering a vital interaction between SDHAF3 and SDHB. We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.
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