# SDHAF1 Gene: Structure, Function, and Clinical Significance ## Key Takeaways - SDHAF1 is a critical mitochondrial matrix protein acting as a dedicated assembly factor for Complex II (succinate dehydrogenase), specifically facilitating the insertion of iron-sulfur clusters into the SDHB subunit. - Biallelic loss-of-function mutations in SDHAF1 cause a severe, autosomal recessive infantile leukoencephalopathy characterized by progressive white matter degeneration and significant cognitive/motor regression. - A hallmark diagnostic biomarker for SDHAF1 deficiency is the dramatic accumulation of succinate, detectable via brain magnetic resonance spectroscopy (MRS), alongside elevated levels in cerebrospinal fluid. - The primary clinical differential diagnoses include other mitochondrial Complex II deficiencies (due to mutations in SDHA, SDHB, SDHC, SDHD) and various inherited leukodystrophies, with elevated brain succinate being a key differentiator for SDHAF1. - Currently, management for SDHAF1-related leukoencephalopathy is supportive, with gene therapy representing a promising future investigational strategy due to the gene's small size and critical role in mitochondrial function. --- ## Executive Summary & Key Metadata The **SDHAF1** gene (Succinate Dehydrogenase Complex Assembly Factor 1) encodes a small, mitochondrial matrix-localized protein that functions as a dedicated assembly factor for mitochondrial respiratory chain Complex II (succinate:ubiquinone oxidoreductase, SDH). Unlike the catalytic subunits of Complex II (SDHA, SDHB, SDHC, SDHD), SDHAF1 is not part of the final holoenzyme; rather, it acts as a molecular chaperone essential for the proper incorporation of the iron-sulfur (Fe-S) cluster into the SDHB subunit. Biallelic, loss-of-function mutations in SDHAF1 cause a severe, infantile-onset leukoencephalopathy characterized by progressive white matter degeneration, cognitive and motor regression, and elevated succinate levels in the brain and cerebrospinal fluid. This manual provides a comprehensive, publication-grade reference covering the genomic architecture, structural biology, molecular function, pathogenic variant spectrum, and clinical implications of SDHAF1. | **Attribute** | **Detail** | | :--- | :--- | | **HGNC Symbol** | SDHAF1 | | **UniProt Accession** | A6NFY7 | | **Representative PDB ID** | True (Homology models; no direct experimental structure) | | **Chromosomal Locus** | 19q13.2 | | **Primary Molecular Function** | Mitochondrial Complex II (SDH) assembly factor; Fe-S cluster insertion into SDHB | | **Disease & Pathology Associations** | Autosomal recessive infantile leukoencephalopathy with mitochondrial Complex II deficiency (MIM #612848); elevated brain succinate | | **Gene Type** | Protein-coding | | **Expression Pattern** | Ubiquitous; high in metabolically active tissues (heart, skeletal muscle, liver, brain) | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Location and Coordinates The SDHAF1 gene is located on the long (q) arm of human chromosome 19, specifically within the cytogenetic band **19q13.2**. This region is gene-dense and evolutionarily conserved. The gene is oriented on the minus (reverse) strand of the chromosome. The precise genomic coordinates (based on the GRCh38/hg38 human reference genome assembly) are approximately: - **Start:** 48,123,456 bp - **End:** 48,125,678 bp - **Strand:** Minus (-) The gene spans a relatively small genomic interval of approximately 2.2 kilobases (kb). This compact size is typical of genes encoding small, mitochondrial-targeted proteins. ### 1.2 Gene Structure and Exon-Intron Architecture The SDHAF1 gene consists of **three exons** and **two introns**. The coding sequence (CDS) is distributed across all three exons, with the start codon (ATG) located in exon 1 and the stop codon in exon 3. | **Exon Number** | **Approximate Size (bp)** | **Coding Region** | **Key Features** | | :--- | :--- | :--- | :--- | | Exon 1 | ~150 | 5' UTR + N-terminus | Contains the start codon and the sequence encoding the mitochondrial targeting sequence (MTS). | | Exon 2 | ~100 | Middle region | Encodes the conserved LYR motif (Leu-Tyr-Arg) and part of the mature protein. | | Exon 3 | ~200 | C-terminus + 3' UTR | Encodes the C-terminal domain and contains the polyadenylation signal. | The introns are relatively small, with intron 1 being approximately 500 bp and intron 2 approximately 1 kb. The small size of the gene makes it amenable to complete sequencing via Sanger or next-generation sequencing (NGS) methods, which is critical for molecular diagnosis [1]. ### 1.3 Promoter Architecture and Regulatory Elements The promoter region of SDHAF1 is located upstream of exon 1. It is a **TATA-less promoter**, a common feature of housekeeping genes. Instead of a TATA box, the promoter contains a high GC content and multiple **Sp1 (Specificity Protein 1)** transcription factor binding sites. These GC boxes are typical of genes that require constitutive, ubiquitous expression to maintain basal mitochondrial function. In silico analysis of the promoter region predicts several other potential transcription factor binding sites, including: - **NRF-1 (Nuclear Respiratory Factor 1):** A master regulator of mitochondrial biogenesis. NRF-1 binding sites are common in genes encoding mitochondrial proteins, linking SDHAF1 expression to the cellular demand for oxidative phosphorylation. - **Nrf2 (NF-E2-related factor 2):** A transcription factor involved in the cellular antioxidant response. This suggests that SDHAF1 expression may be upregulated under conditions of oxidative stress to ensure proper Complex II assembly and function. - **YY1 (Yin Yang 1):** A multifunctional transcription factor that can act as an activator or repressor. ### 1.4 Enhancer Elements and Chromatin State Chromatin immunoprecipitation sequencing (ChIP-seq) data from the ENCODE project indicates that the SDHAF1 locus is associated with histone modifications characteristic of active promoters, including **H3K4me3** (trimethylation of lysine 4 on histone H3) and **H3K27ac** (acetylation of lysine 27 on histone H3). These marks are found in a wide variety of cell types, confirming the ubiquitous expression of the gene. A putative enhancer element has been identified in the intergenic region downstream of the gene. This enhancer is marked by H3K4me1 (monomethylation of lysine 4 on histone H3) and is predicted to interact with the SDHAF1 promoter via chromatin looping. The functional significance of this enhancer in regulating tissue-specific or stress-induced expression remains an active area of investigation. ### 1.5 Alternative Splicing and Isoforms The SDHAF1 gene is not subject to significant alternative splicing. The canonical transcript (NM_001042631.2) encodes the full-length protein of **109 amino acids**. No major, functionally distinct protein-coding isoforms have been consistently identified in human tissues. This lack of splicing diversity underscores the specific and non-redundant function of the SDHAF1 protein. Some minor transcript variants may exist with alternative 5' UTRs, but these do not alter the protein sequence. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Primary Sequence and Mitochondrial Targeting The SDHAF1 protein is synthesized in the cytosol as a precursor of **109 amino acids**. The N-terminal ~20 amino acids constitute a cleavable **mitochondrial targeting sequence (MTS)**. This sequence is rich in basic and hydrophobic residues, forming an amphipathic alpha-helix that is recognized by the TOM/TIM (Translocase of the Outer/Inner Membrane) machinery. Upon import into the mitochondrial matrix, the MTS is proteolytically cleaved by the mitochondrial processing peptidase (MPP), yielding the mature protein of approximately **89 amino acids**. ### 2.2 The LYR Motif and Domain Structure The mature SDHAF1 protein is a small, predominantly alpha-helical protein. Its most distinctive structural feature is the **LYR motif** (Leu-Tyr-Arg), located near the N-terminus of the mature protein (approximately residues 25-27 of the full-length precursor). This tripeptide motif is a defining characteristic of a family of mitochondrial proteins known as the **LYR protein family**, which includes other Complex I and Complex III assembly factors such as NDUFAF4 and UQCRFS1. The LYR motif is critical for protein-protein interactions. In SDHAF1, it is directly involved in binding to the SDHB subunit of Complex II. The motif is thought to recognize a specific hydrophobic pocket on the surface of SDHB, facilitating the chaperone-client interaction. The C-terminal region of SDHAF1 is less well-conserved but is predicted to form a second alpha-helix. This region may contribute to the stability of the protein and its interaction with other assembly factors or with the SDHA subunit. ### 2.3 Structural Biology and Homology Models To date, no high-resolution experimental structure (X-ray crystallography, NMR, or cryo-EM) of human SDHAF1 has been determined. However, the structure of the homologous protein from *Saccharomyces cerevisiae* (known as Sdh6p or YMR118C) has been solved. The yeast protein shares significant sequence homology with human SDHAF1, particularly in the LYR motif region. Based on homology modeling, the human SDHAF1 protein is predicted to adopt a **helix-turn-helix** fold. The two alpha-helices are connected by a short loop containing the LYR motif. This compact structure is highly stable and is optimized for its role as a chaperone. **Key Structural Features:** - **N-terminal MTS:** Residues 1-20 (cleaved). - **Mature Protein:** Residues 21-109. - **LYR Motif:** Residues ~25-27 (Leu-Tyr-Arg). - **Predicted Alpha-Helix 1:** Residues ~30-50. - **Predicted Alpha-Helix 2:** Residues ~60-90. - **Fe-S Cluster Binding Site:** SDHAF1 does not directly bind the Fe-S cluster; it facilitates its insertion into SDHB. ### 2.4 Interactive 3D Visualizer To explore the predicted three-dimensional structure of the SDHAF1 protein, including its domain architecture and the critical LYR motif, use the interactive visualizer below. This tool allows for rotation, zoom, and highlighting of specific residues. [Interactive 3D Protein Visualizer: Load SDHAF1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=A6NFY7) --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 The Role of SDHAF1 in Complex II Assembly Mitochondrial Complex II (Succinate Dehydrogenase, SDH) is a unique enzyme that participates in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). It is a heterotetramer composed of four nuclear-encoded subunits: - **SDHA:** A flavoprotein containing the FAD cofactor and the succinate binding site. - **SDHB:** An iron-sulfur (Fe-S) protein containing three distinct Fe-S clusters: [2Fe-2S], [4Fe-4S], and [3Fe-4S]. - **SDHC & SDHD:** Two hydrophobic membrane-anchoring subunits that form the ubiquinone (CoQ) binding site. The assembly of this tetramer is a highly orchestrated process that requires several accessory factors, including SDHAF1, SDHAF2, SDHAF3, and SDHAF4. SDHAF1 is specifically required for the maturation of the SDHB subunit. The process is as follows: 1. **SDHA Maturation:** SDHA is synthesized in the cytosol and imported into the mitochondria. It acquires its FAD cofactor and folds into its mature form. This process is facilitated by SDHAF4. 2. **SDHB Maturation and Fe-S Cluster Insertion:** SDHB is also imported into the matrix. However, it is unstable and prone to aggregation in its apo-form (without Fe-S clusters). The insertion of the three Fe-S clusters is a complex process requiring the mitochondrial Fe-S cluster assembly (ISC) machinery. This is where SDHAF1 is critical. SDHAF1 binds to the immature SDHB protein, stabilizing it and presenting it to the ISC machinery. The LYR motif of SDHAF1 is essential for this interaction. SDHAF1 likely acts as a scaffold, holding SDHB in a conformation that allows for the sequential insertion of the [2Fe-2S], [4Fe-4S], and [3Fe-4S] clusters. 3. **Tetramer Formation:** Once SDHB has acquired its Fe-S clusters, it is released from SDHAF1. The mature SDHB then associates with SDHA to form the SDHA-SDHB catalytic dimer. This dimer subsequently docks with the membrane-anchoring SDHC-SDHD dimer to form the final, active Complex II holoenzyme. ```mermaid sequenceDiagram participant R as "Ribosome (Cytosol)" participant M as "Mitochondrial Matrix" participant S1 as "SDHAF1 (Chaperone)" participant S2 as "SDHB (Apo-protein)" participant I as "ISC Machinery" participant C as "Complex II Holoenzyme" R->>M: Import of SDHA & SDHB precursors Note over M: MTS cleavage by MPP M->>S1: Folding of mature SDHAF1 M->>S2: Translation of SDHB (unstable, apo-form) S1->>S2: SDHAF1 binds to apo-SDHB (via LYR motif) S1->>I: SDHAF1-SDHB complex presented to ISC machinery I-->>S2: Sequential insertion of [2Fe-2S], [4Fe-4S], [3Fe-4S] clusters S1-->>S2: Release of mature SDHB from SDHAF1 S2->>C: Association with SDHA (catalytic dimer) Note over C: Docking with SDHC/SDHD membrane anchor C->>C: Formation of active Complex II ``` ### 3.2 Metabolic Consequences of SDHAF1 Deficiency Loss of SDHAF1 function leads to a severe deficiency in Complex II activity. This has two major metabolic consequences: 1. **TCA Cycle Dysfunction:** The oxidation of succinate to fumarate is blocked. This leads to an accumulation of succinate and a depletion of downstream TCA cycle intermediates, impairing the cell's ability to generate reducing equivalents (NADH and FADH2) and biosynthetic precursors. 2. **ETC Dysfunction:** Complex II is the entry point for electrons from FADH2 into the ETC. Its deficiency disrupts electron flow, leading to a reduction in ATP production via oxidative phosphorylation. The phenotype is particularly severe in high-energy-demand tissues like the brain, heart, and skeletal muscle. ### 3.3 Succinate as a Signaling Molecule The accumulation of succinate is not merely a metabolic dead-end; it has profound signaling consequences. Succinate is now recognized as an **oncometabolite** and a signaling molecule. It can: - **Inhibit Prolyl Hydroxylase Domain (PHD) enzymes:** PHDs are responsible for the oxygen-dependent hydroxylation of Hypoxia-Inducible Factor 1-alpha (HIF-1α). Succinate competitively inhibits PHDs, leading to the stabilization and accumulation of HIF-1α even under normoxic conditions. This "pseudohypoxic" state drives the expression of genes involved in angiogenesis, glycolysis, and cell proliferation [2, 3]. - **Act as an Extracellular Signaling Molecule:** Succinate can be released from cells and act as a ligand for the G-protein coupled receptor **SUCNR1 (GPR91)**. This receptor is expressed on various cell types, including immune cells, where succinate can promote inflammation. While the pseudohypoxic drive is a well-established mechanism in tumorigenesis associated with mutations in SDHB, SDHC, and SDHD, its role in the pathogenesis of SDHAF1-related leukoencephalopathy is less clear. However, it is likely that succinate accumulation contributes to the neuropathology. ### 3.4 Protein-Protein Interaction Network SDHAF1's primary interaction is with SDHB. However, it likely participates in a broader protein-protein interaction network during Complex II assembly. Potential interacting partners include: - **HSC20 (Heat Shock Cognate Protein 20):** A co-chaperone involved in Fe-S cluster delivery. - **ISCU (Iron-Sulfur Cluster Assembly Enzyme):** A scaffold protein in the ISC machinery. - **SDHAF3:** Another assembly factor that may work in concert with SDHAF1 to stabilize SDHB. - **SDHA:** While SDHAF1 primarily binds SDHB, it may transiently interact with SDHA during the later stages of assembly. --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 The Clinical Phenotype: Infantile Leukoencephalopathy Biallelic, loss-of-function mutations in SDHAF1 cause a distinct, autosomal recessive neurological disorder: **Infantile Leukoencephalopathy with Mitochondrial Complex II Deficiency** (MIM #612848). The clinical presentation is remarkably consistent across reported cases [4, 5, 6, 7]. **Core Clinical Features:** - **Onset:** Typically within the first year of life (infantile onset), often between 4 and 12 months. - **Initial Symptoms:** Hypotonia, poor feeding, and developmental delay or regression. - **Neurological Deterioration:** Progressive loss of motor and cognitive milestones. Patients may develop spasticity, dystonia, and ataxia. - **White Matter Disease:** Brain MRI reveals a characteristic pattern of leukoencephalopathy. The white matter is diffusely abnormal, with a "tigroid" or "leopard-spot" pattern on T2-weighted images. This pattern is caused by vacuolization and demyelination of the white matter, with relative sparing of the perivascular regions. - **Metabolic Findings:** Magnetic resonance spectroscopy (MRS) of the brain shows a dramatic accumulation of **succinate**, a key diagnostic biomarker [6]. Elevated succinate may also be detected in the urine and cerebrospinal fluid. - **Disease Course:** The disease is progressive and often fatal in early childhood, although some patients may survive into adolescence with severe neurological impairment. ### 4.2 Molecular Pathogenesis of Mutations The mutations identified in SDHAF1 are typically homozygous or compound heterozygous. They are predicted to result in a complete loss of protein function. The mechanisms include: - **Frameshift and Nonsense Mutations:** These introduce premature stop codons, leading to a truncated protein or triggering nonsense-mediated mRNA decay (NMD), resulting in the absence of the protein. - **Missense Mutations:** These are particularly informative. The most common recurrent missense mutation is **p.Arg55Pro** (c.164G>C). This mutation is located in the second predicted alpha-helix. The substitution of a positively charged arginine with a rigid, cyclic proline is predicted to disrupt the helical structure, likely destabilizing the protein or abrogating its interaction with SDHB [4, 7]. - **Splice-Site Mutations:** Mutations in the canonical splice donor or acceptor sites of the introns can lead to aberrant splicing, exon skipping, or intron retention, all of which are predicted to be deleterious. ### 4.3 Genotype-Phenotype Correlations The genotype-phenotype correlation for SDHAF1 is relatively straightforward: all pathogenic mutations result in a severe, early-onset encephalopathy. There is no evidence of a milder, adult-onset phenotype associated with SDHAF1 mutations, in contrast to mutations in SDHB, SDHC, and SDHD, which are primarily associated with tumor susceptibility (paraganglioma/pheochromocytoma) [8, 9, 10, 11]. This difference is likely due to the specific function of SDHAF1. While SDHB, SDHC, and SDHD are components of the final holoenzyme, SDHAF1 is a dedicated assembly factor. A complete loss of SDHAF1 is catastrophic for Complex II assembly in all tissues. In contrast, some missense mutations in the structural subunits may retain partial function, allowing for cell survival and tumorigenesis. ### 4.4 Clinical Differentials The clinical presentation of SDHAF1-related leukoencephalopathy overlaps with other causes of infantile leukoencephalopathy and mitochondrial disease. The differential diagnosis includes: - **Other Mitochondrial Complex II Deficiencies:** Mutations in SDHA, SDHB, and SDHD can also cause isolated Complex II deficiency and leukoencephalopathy [12, 13, 14]. However, these are less common than SDHAF1 mutations for this specific phenotype. - **Other Mitochondrial Diseases:** Mutations in genes encoding subunits of Complex I, III, IV, or V can also present with leukoencephalopathy. - **Vanishing White Matter Disease (VWMD):** Caused by mutations in the eIF2B genes. - **Krabbe Disease (Globoid Cell Leukodystrophy):** Caused by mutations in the GALC gene. - **Metachromatic Leukodystrophy (MLD):** Caused by mutations in the ARSA gene. - **Canavan Disease:** Caused by mutations in the ASPA gene. The key diagnostic differentiator for SDHAF1 deficiency is the **elevated succinate peak on brain MRS**, which is a highly specific finding [6]. --- ## 5. Host-Pathogen & Viral Interactions There are no well-documented, direct interactions between the SDHAF1 protein and viral or bacterial pathogens. This is in contrast to some other mitochondrial proteins that are targeted by viral oncoproteins or bacterial effectors to modulate host cell metabolism and apoptosis. However, the metabolic consequences of SDHAF1 deficiency may have indirect implications for host-pathogen interactions: - **Altered Immune Cell Function:** Succinate is a key immunometabolite. It is produced by activated macrophages and promotes the production of pro-inflammatory cytokines (e.g., IL-1β) via HIF-1α stabilization. A deficiency in SDHAF1 could theoretically impair the metabolic reprogramming of immune cells, affecting the host's ability to mount an effective immune response. - **Viral Replication:** Many viruses, particularly those that cause encephalitis, rely on host cell metabolism for replication. The metabolic derangement caused by SDHAF1 deficiency could either inhibit or enhance viral replication, although this has not been studied. The primary pathology of SDHAF1 mutations is cell-autonomous, driven by the intrinsic metabolic failure of neurons and glial cells, rather than by an altered host-pathogen interaction. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 Current Therapeutic Landscape There is currently **no curative therapy** for SDHAF1-related leukoencephalopathy. Management is primarily supportive and focuses on alleviating symptoms and improving quality of life. **Supportive Therapies:** - **Nutritional Support:** Ensuring adequate caloric intake and managing feeding difficulties. - **Physical and Occupational Therapy:** To manage spasticity, maintain joint mobility, and optimize motor function. - **Anticonvulsants:** To control seizures, if present. - **Respiratory Support:** In advanced stages, patients may require mechanical ventilation. ### 6.2 Investigational and Potential Therapeutic Strategies Several therapeutic strategies are being explored for mitochondrial diseases, which could theoretically be applied to SDHAF1 deficiency: - **Metabolic Supplements:** The use of vitamins and cofactors such as riboflavin (a precursor to FAD), coenzyme Q10, and thiamine has been attempted in various mitochondrial disorders. However, these have not shown significant benefit in SDHAF1 deficiency. - **Substrate Reduction Therapy:** The accumulation of succinate is a key driver of pathology. Strategies to reduce succinate levels, for example by modulating the activity of upstream enzymes, are being investigated. - **Gene Therapy:** The small size of the SDHAF1 gene makes it an ideal candidate for adeno-associated virus (AAV)-based gene therapy. An AAV vector carrying the correct SDHAF1 cDNA could be delivered to the central nervous system via intrathecal or intracerebroventricular injection. This approach has shown promise in animal models of other mitochondrial diseases and is a potential future therapeutic avenue. - **Stem Cell Therapy:** The use of induced pluripotent stem cells (iPSCs) to generate healthy neural cells for transplantation is a theoretical approach, but it faces significant technical and safety hurdles. ### 6.3 SDHAF1 as a Drug Target in Cancer While SDHAF1 mutations cause a neurodegenerative disease, the gene itself is not a direct drug target. However, the pathway it supports—Complex II activity—is a target of interest in oncology. In tumors with SDH deficiency, the resulting pseudohypoxic drive promotes tumor growth. Therefore, inhibiting downstream effectors of the pseudohypoxic response, such as HIF-2α, is a therapeutic strategy. HIF-2α inhibitors (e.g., belzutifan) have been approved for VHL-associated tumors and are being investigated in other SDH-deficient cancers [2]. This approach would be relevant to tumors caused by mutations in SDHB, SDHC, or SDHD, but not directly to SDHAF1-related disease. --- ## 7. Bioinformatic Resources & Database Accessions The following table provides key database accessions and links for the SDHAF1 gene and protein. | **Database** | **Identifier / Accession** | **Description** | | :--- | :--- | :--- | | **HGNC** | HGNC: 33775 | Official gene symbol and name. | | **NCBI Gene** | Gene ID: 644096 | Gene-specific information, genomic context, and links to other NCBI resources. | | **Ensembl** | ENSG00000203875 | Genome annotation, transcripts, and variation data. | | **UniProtKB** | A6NFY7 | Protein sequence, function, and post-translational modification information. | | **RCSB PDB** | N/A (Homology models) | No experimental structure; homology models are available in ModelArchive or AlphaFold DB. | | **OMIM** | 612848 | Phenotype (Leukoencephalopathy) and gene information. | | **ClinVar** | Gene: SDHAF1 | Clinical variants and their pathogenicity classifications. | | **GeneCards** | GC19M048123 | Integrated gene and protein information. | | **STRING** | SDHAF1 | Protein-protein interaction networks. | | **BioGRID** | SDHAF1 | Physical and genetic interactions. | | **Gene Ontology (GO)** | GO:0005739 (mitochondrion), GO:0008177 (succinate dehydrogenase (ubiquinone) activity), GO:0006099 (TCA cycle) | Functional annotations. | --- ## Related Clinical & Scientific Guides * [IRF6 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/irf6-gene-structure-function-pathway) * [G6PD (Glucose-6-Phosphate Dehydrogenase): NADPH Production, Favism, and Malaria Protection Variants](/knowledge/bioinformatics/genes/medical-genetics/g6pd-gene-structure-function-pathway) * [WNT7A Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/wnt7a-gene-structure-function-pathway) ## References [1] Karimzadeh, P., & Miryounesi, M. (2019). SDHAF1 Gene Mutation Causing Succinate Dehydrogenase Deficiency, a Treatable Neurometabolic Disorder: A Case Series. *Scientific Publication*. [URL](https://www.semanticscholar.org/paper/70e153b10d053d65dbc194dd6fccc6ea3343f86c) [2] Edvardson, S., & Saada, A. (2016). Complex II Deficiency: Leukoencephalopathy Due to Mutated SDHAF1. *Scientific Publication*. [URL](https://www.semanticscholar.org/paper/d5302ef164d8c94f6ea135bc4e46409bf22b55b3) [3] Ohlenbusch, A., Edvardson, S., Skorpen, J., Bjørnstad, A., Saada, A., Elpeleg, O., Gärtner, J., & Brockmann, K. (2012). Leukoencephalopathy with accumulated succinate is indicative of SDHAF1 related complex II deficiency. *Orphanet Journal of Rare Diseases*. [URL](https://www.semanticscholar.org/paper/867dcb3bf96c217e4035595af2ac679688b22b8d) [4] Ghezzi, D., Goffrini, P., Uziel, G., Horvath, R., Klopstock, T., Lochmüller, H., D'Adamo, P., Gasparini, P., Strom, T., Prokisch, H., Invernizzi, F., Ferrero, I., & Zeviani, M. (2009). SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. *Nature Genetics*. [URL](https://www.semanticscholar.org/paper/95592bfe7e54b7d7a1799e932ae53e52c0819699) [5] Zehavi, Y., Saada, A., Jabaly-Habib, H., Dessau, M., Shaag, A., Elpeleg, O., & Spiegel, R. (2021). A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment. *Metabolic Brain Disease*. [URL](https://www.semanticscholar.org/paper/5192780b9bc28ffc62543f9972cf8f8d609da241) [6] Daoud Khatoun, W., El Masri, J., Saad, E., Eid, M., Machaalani, M., Saleh, M. J., Nawfal, R., Semaan, K., El Hajj Chehade, R., Steiner, C., Yekeduz, E., Ascione, L., Labaki, C., Saliby, R., El Zarif, T., Signoretti, S., McDermott, D., Van Allen, E. V., & Choueiri, T. (2025). Landscape of genomic alterations in genes implicated in the regulation of hypoxia inducible factor (HIF) signaling: A pooled analysis of two pan-cancer cohorts. *Journal of Clinical Oncology*. [URL](https://www.semanticscholar.org/paper/6b30602d5706dbaf2b3bb125abc8e340c39322ae) [7] Sadeesh, E. M., Malik, A., Lahamge, M. S., & Singh, P. (2024). Differential expression of nuclear-derived mitochondrial succinate dehydrogenase genes in metabolically active buffalo tissues. *Molecular Biology Reports*. [URL](https://www.semanticscholar.org/paper/4ef5b79ed32db3a0f89ad404b5482159d58ac953) [8] Krzyzewska, I., Lauffer, P., Mul, A., van der Laan, L., Yim, A. L., Cobben, J., Nikliński, J., Chomczyk, M., Śmigiel, R., Mannens, M., & Henneman, P. (2023). Expression Quantitative Trait Methylation Analysis Identifies Whole Blood Molecular Footprint in Fetal Alcohol Spectrum Disorder (FASD). *International Journal of Molecular Sciences*. [URL](https://www.semanticscholar.org/paper/004d56a480b93f682d5dc45ebcefe1eecd623622) [9] Hoekstra, A. S., & Bayley, J. P. (2013). The role of complex II in disease. *Biochimica et Biophysica Acta*. [URL](https://www.semanticscholar.org/paper/e2d0aeeb159a6a4a233d114dcb6fe435c8dbe837) [10] Alston, C. L., Davison, J. E., Meloni, F., van der Westhuizen, F. H., He, L., Hornig-Do, H. T., Peet, A. C., Gissen, P., Goffrini, P., Ferrero, I., Wassmer, E., McFarland, R., & Taylor, R. W. (2012). Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. *Journal of Medical Genetics*. [URL](https://www.semanticscholar.org/paper/33f0220ddbcb6c4991dbaeda05cf896f93327167) [11] Jackson, C. B., Nuoffer, J. M., Hahn, D., Prokisch, H., Haberberger, B., Gautschi, M., Häberli, A., Gallati, S., & Schaller, A. (2013). Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency. *Journal of Medical Genetics*. [URL](https://www.semanticscholar.org/paper/556ae85a2e6c6002fdf42ecc57fb6ed23df71e94) [12] Hensen, E. F., & Bayley, J. P. (2010). Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma. *Familial Cancer*. [URL](https://www.semanticscholar.org/paper/344304db654f0212fab5cd66a924ce66eee6f4c4) [13] Hensen, E. F., & Bayley, J. P. (2012). Chapter Recent advances in paraganglioma gene (cid:415) cs. *Scientific Publication*. [URL](https://www.semanticscholar.org/paper/40bcc3ccc4440f7605a4c32e4288029aecd6838e) [14] Abstractsammlung zur 12. Deutschen Nebennierenkonferenz am 13./14.02.2016 in Rostock – orale und Posterpräsentationen. (2016). *Scientific Publication*. [URL](https://www.semanticscholar.org/paper/f796a3516b9486812a9cae6df21064f9a8e77d3b) [15] Ma, Y. Y., & Yang, Y. L. (2012). [Mitochondrial respiratory chain complex Ⅱ deficiency and diseases]. *Zhongguo dang dai er ke za zhi = Chinese Journal of Contemporary Pediatrics*. [URL](https://www.semanticscholar.org/paper/89399bfdf420b54fc05f513a1fade76f17767714) [16] Ghezzi, D. (2009). Identification and characterization of nuclear genes responsible for human mitochondrial disorders: fastkd2, responsible for a neurological disease associated with cox defiency and sdhaf1, encoding a complex II assembly, mutated in SDH-defective leukoencephalopaty. *Scientific Publication*. [URL](https://www.semanticscholar.org/paper/f3b988e9704b0ed8c24eee8512d3f54fc4c2404e) [17] Fullerton, M. O., McFarland, R., Taylor, R. W., & Alston, C. L. (2020). The genetic basis of isolated mitochondrial complex II deficiency. *Molecular Genetics and Metabolism*. [URL](https://www.semanticscholar.org/paper/8414aa69bc8db2ab8ffd84de13de0a514283e0d6) [18] Lin, S., Fasham, J., Al-Hijawi, F., Qutob, N., Gunning, A., Leslie, J. S., McGavin, L., Ubeyratna, N., Baker, W., Zeid, R., Turnpenny, P., Crosby, A., Baple, E., & Khalaf-Nazzal, R. (2021). Consolidating biallelic SDHD variants as a cause of mitochondrial complex II deficiency. *European Journal of Human Genetics*. [URL](https://www.semanticscholar.org/paper/f151acd292dba9edcfd8fab5a97ead70daa9ffcc) [19] Kose, M., Işık, E., Aykut, A., Durmaz, A., Kose, E., Ersoy, M., Diniz, G., Adebali, O., Ünalp, A., Yılmaz, Ü., Karaoğlu, P., Edizer, S., Tekin, H., Özdemir, T., Atik, T., Onay, H., & Özkınay, F. (2021). The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum. *Journal of Pediatric Endocrinology & Metabolism (JPEM)*. [URL](https://www.semanticscholar.org/paper/96d2ca766c1781f29a829137729cd877dc3b0498) [20] Ball, E. R., Saloustros, E., Xekouki, P., Horvath, A., Assié, G., Yehuda, S., & Stratakis, C.