SDHD Gene - Succinate Dehydrogenase Complex Subunit D
SDHD: A key tumor suppressor gene in mitochondrial complex II, associated with hereditary paraganglioma-pheochromocytoma syndromes and gastrointestinal stromal tumors.
Gene Information Card
| Symbol | SDHD |
|---|---|
| Full Name | Succinate Dehydrogenase Complex Subunit D |
| Gene Type | Protein coding |
| Chromosomal Location | 11q23.1 |
| NCBI Gene ID | 6392 ncbi.nlm.nih.gov/gene/6392 |
| Ensembl ID | ENSG00000100219 |
| UniProt ID | O14521 |
| OMIM ID | 602690 |
| HGNC ID | 10683 |
| Aliases | PGL, PGL1, QPs3, CII-4, SDH4, CYB560, DHSB, IP, PGL1, SDH, SDHD |
Description
The SDHD gene encodes the small subunit (cybS) of succinate dehydrogenase (SDH), also known as mitochondrial complex II. This enzyme couples the oxidation of succinate to fumarate in the tricarboxylic acid (TCA) cycle with the reduction of ubiquinone to ubiquinol in the electron transport chain. SDHD is a tumor suppressor; germline loss-of-function mutations predispose to hereditary paraganglioma-pheochromocytoma syndrome type 1 (PGL1) and gastrointestinal stromal tumors (GIST). The gene is imprinted with paternal expression in some tissues, leading to parent-of-origin effects in disease transmission.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hereditary Paraganglioma-Pheochromocytoma Syndrome Type 1 (PGL1) | Germline loss-of-function mutations in SDHD lead to succinate accumulation, stabilization of HIF1α, and pseudohypoxic signaling, promoting tumorigenesis in paraganglia and adrenal medulla. | OMIM #168000; ClinVar; NCBI Gene |
| Gastrointestinal Stromal Tumor (GIST) | SDHD mutations cause succinate dehydrogenase-deficient GISTs, characterized by loss of SDHB expression and activation of IGF1R signaling. | OMIM #606764; ClinVar; COSMIC |
| Renal Cell Carcinoma (RCC) | SDHD mutations are associated with a rare form of renal cell carcinoma, often with clear cell or chromophobe histology, via similar pseudohypoxic mechanisms. | OMIM #614287; ClinVar |
| Pituitary Adenoma | Rarely, SDHD mutations have been reported in pituitary adenomas, likely through dysregulated hypoxia signaling. | ClinVar; literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Heart | 12.5 | Medium |
| Skeletal Muscle | 10.8 | Medium |
| Liver | 8.2 | Medium |
| Kidney | 7.9 | Medium |
| Brain | 6.5 | Low |
| Adrenal Gland | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 15.3 | High expression |
| HeLa | 12.1 | Medium expression |
| HepG2 | 10.4 | Medium expression |
| A549 | 8.7 | Medium expression |
| K562 | 6.2 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.274G>T (p.Asp92Tyr) | Missense | ~5% in PGL1 | Loss of function; disrupts ubiquinone binding |
| c.337_340delGACT (p.Asp113Metfs*15) | Frameshift | ~10% in PGL1 | Loss of function; premature truncation |
| c.34G>A (p.Gly12Ser) | Missense | <1% | Loss of function; reduced SDH activity |
| c.1A>G (p.Met1Val) | Start loss | Rare | Loss of function; no protein translation |
| c.298T>C (p.Cys100Arg) | Missense | <1% | Loss of function; impaired complex assembly |
Mutation functional classification
Loss of Function (LOF)
The majority of SDHD mutations are loss-of-function, leading to reduced or absent SDH enzyme activity, succinate accumulation, and pseudohypoxic signaling. These are typically germline and associated with hereditary tumor syndromes.
Gain of Function (GOF)
No gain-of-function mutations have been reported for SDHD.
Dominant Negative (DN)
Some missense mutations may exert a dominant-negative effect by disrupting complex II assembly, but evidence is limited; most act via haploinsufficiency or complete loss of function.
View complete mutation data：
Gene Ontology (GO)
| • GO:0008177 - succinate dehydrogenase (ubiquinone) activity | • GO:0006120 - mitochondrial electron transport |
| • succinate to ubiquinone | • GO:0006099 - tricarboxylic acid cycle |
| • GO:0005739 - mitochondrion | • GO:0005743 - mitochondrial inner membrane |
| • GO:0045252 - succinate dehydrogenase complex (ubiquinone) | • GO:0006915 - apoptotic process |
| • GO:0001666 - response to hypoxia |
Pathways
• KEGG: hsa00020 - Citrate cycle (TCA cycle)
• KEGG: hsa00190 - Oxidative phosphorylation
• KEGG: hsa05012 - Parkinson disease
• KEGG: hsa05016 - Huntington disease
• KEGG: hsa05010 - Alzheimer disease
• Reactome: R-HSA-1428517 - The citric acid (TCA) cycle and respiratory electron transport
• Reactome: R-HSA-611105 - Respiratory electron transport
Protein Summary
SDHD (succinate dehydrogenase complex subunit D) is a 159-amino acid protein (17 kDa) that forms the membrane-anchoring subunit of mitochondrial complex II. It contains three transmembrane helices and a heme b prosthetic group, which is essential for electron transfer from succinate to ubiquinone. SDHD is encoded by a nuclear gene and imported into mitochondria. Loss of SDHD function leads to succinate accumulation, which inhibits prolyl hydroxylases, stabilizes HIF1α, and drives a pseudohypoxic transcriptional program promoting angiogenesis, glycolysis, and tumor growth. SDHD is subject to genomic imprinting, with preferential expression from the paternal allele in certain tissues, explaining the parent-of-origin inheritance pattern in PGL1.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SDHD Knockout HEK293 Cell Line | EDJ-KQ50619 | Human | 6392 | Details Get a Quote |
| SDHD Knockout HeLa Cell Line | EDJ-KQ54437 | Human | 6392 | Details Get a Quote |
| SDHD Knockout A-549 Cell Line | EDJ-KQ62926 | Human | 6392 | Details Get a Quote |
| SDHD Knockout HCT 116 Cell Line | EDJ-KQ71397 | Human | 6392 | Details Get a Quote |
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