Alternative titles; symbols
HGNC Approved Gene Symbol: SDHAF2
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38) : 11:61,430,124-61,446,733 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.2 | Pheochromocytoma/paraganglioma syndrome 2 | 601650 | Autosomal dominant | 3 |
The SDHAF2 gene encodes a protein necessary for the flavination of the succinate dehydrogenase complex subunit SDHA (600857) and thus for SDH activity (Hao et al., 2009).
By screening for proteins with sequence similarity to yeast Sdh5, Hao et al. (2009) identified human SDH5 as C11ORF79. The amino acid sequence of yeast Sdh5 is 44% identical from residues 33 to 158 of 163 to its human ortholog. The human SDH5 gene encodes a highly conserved 167-amino acid protein. Yeast Sdh5 localizes to the mitochondrial matrix. Both yeast and human SDH5 interact with the catalytic subunit of the succinate dehydrogenase complex, a component of both the electron transport chain and the tricarboxylic acid cycle. SDH5 is required for SDH-dependent respiration and for flavination (incorporation of the flavin adenine dinucleotide cofactor) of SDH1 (SDHA).
Hao et al. (2009) mapped the SDHAF2 gene to chromosome 11q13.1 by genomic sequence analysis.
Pheochromocytoma/Paraganglioma Syndrome 2
In a large Dutch family with hereditary paragangliomas (PPGL2; 601650), originally described by van Baars et al. (1982), Hao et al. (2009) found a missense mutation in the SDH5 gene in the most conserved region of the protein that segregated with the phenotype (G78R; 613019.0001).
In a large Dutch family, originally described by van Baars et al. (1982), segregating autosomal dominant paraganglioma (PPGL2; 601650), Hao et al. (2009) identified a G-to-A transition at nucleotide 232 of exon 2 of the SDHAF2 gene, resulting in a gly-to-arg substitution at codon 78 (G78R). This mutation was not found in 400 unaffected control individuals and segregated with the phenotype in the family. Thirty-three individuals with the mutation had developed the disease, but not 7 individuals (median age 74 years) who had inherited the mutation from their mothers. This suggested an SDHD (602690)-like parent of origin-specific inheritance. Only 5 individuals (median age 42 years) with a paternal mutation had not developed overt paraganglioma. This reduced penetrance was thought to relate to young age and/or presence of undetected tumors.
Hao et al. (2009) found that flavination of SDHA (600857) was decreased by approximately 95% in tumors from 3 patients with the PGL2 G78R mutation in comparison with control tumors from 2 sporadic PGL patients or with cultured human embryonic kidney and hepatoma cells and mouse skeletal cells and liver tissue. Mitochondrial localization of SDH5 was not compromised by this mutation. However, SDH5-G78R dramatically impaired the interaction of SDH5 with SDHA and slightly decreased the level of SDH5 protein. Human SDH5 was able to complement the yeast Sdh5 deletion glycerol growth defect, but human SDH5 carrying the G78R mutant had no effect.
Hensen et al. (2012) identified the Dutch founder G78R mutation in 46 cases from 4 Dutch families out of a larger cohort of 1,045 patients from 340 Dutch families with paraganglioma and pheochromocytoma.
This variant is classified as a variant of unknown significance because its contribution to pheochromocytoma/paraganglioma syndrome (PPGL2; 601650) has not been confirmed.
In 2 unrelated adults with isolated adrenal pheochromocytoma and no family history of a cancer susceptibility syndrome, Casey et al. (2014) identified a heterozygous c.12C-T transition in the 3-prime untranslated region of the SDHAF2 gene. Functional studies of the variant were not performed. The patients were part of a larger retrospective study of 31 individuals with pheochromocytomas or paragangliomas who underwent sequencing of several candidate susceptibility genes.
Casey, R., Garrahy, A., Tuthill, A., O'Halloran, D., Joyce, C., Casey, M. B., O'Shea, P., Bell, M. Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation. J. Clin. Endocr. Metab. 99: E1392-1396, 2014. [PubMed: 24712571] [Full Text: https://doi.org/10.1210/jc.2013-4536]
Hao, H.-X., Khalimonchuk, O., Schraders, M., Dephoure, N., Bayley, J.-P., Kunst, H., Devilee, P., Cremers, C. W. R. J., Schiffman, J. D., Bentz, B. G., Gygi, S. P., Winge, D. R., Kremer H., Rutter, J. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325: 1139-1142, 2009. [PubMed: 19628817] [Full Text: https://doi.org/10.1126/science.1175689]
Hensen, E. F., van Duinen, N., Jansen, J. C., Corssmit, E. P. M., Tops, C. M. J., Romijn, J. A., Vriends, A. H. J. T., van der Mey, A. G. L., Cornelisse, C. J., Devilee, P., Bayley, J. P. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin. Genet. 81: 284-288, 2012. [PubMed: 21348866] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01653.x]
van Baars, F., Cremers, C., van den Broek, P., Geerts, S., Veldman, J. Genetic aspects of nonchromaffin paraganglioma. Hum. Genet. 60: 305-309, 1982. [PubMed: 6286462] [Full Text: https://doi.org/10.1007/BF00569208]