Alternative titles; symbols
HGNC Approved Gene Symbol: SDHD
SNOMEDCT: 722377004;
Cytogenetic location: 11q23.1 Genomic coordinates (GRCh38) : 11:112,086,873-112,095,794 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.1 | Mitochondrial complex II deficiency, nuclear type 3 | 619167 | Autosomal recessive | 3 |
| Paraganglioma and gastric stromal sarcoma | 606864 | 3 | ||
| Pheochromocytoma/paraganglioma syndrome 1 | 168000 | Autosomal dominant | 3 |
The SDHD gene encodes an integral membrane protein subunit of the succinate dehydrogenase (EC 1.3.5.1) complex (summary by Hirawake et al., 1997).
Complex II (succinate-ubiquinone oxidoreductase) is an important enzyme complex in both the tricarboxylic acid cycle and the aerobic respiratory chains of mitochondria in eukaryotic cells and prokaryotic organisms. Hirawake et al. (1997) deduced the amino acid sequences of the large (cybL, encoded by the SDHC gene, 602413) and small (cybS, encoded by the SDHD gene) subunits of cytochrome b in human liver complex II from cDNAs isolated by homology probing with mixed primers for the polymerase chain reaction. The mature cybL and cybS contain 140 and 103 amino acids, respectively, and show little similarity to the amino acid sequences of the subunits from other species, in contrast to the highly conserved features of the flavoprotein (Fp) subunit (SDHA; 600857) and the iron-sulfur protein (Ip) subunit (SDHB; 185470).
Hirawake et al. (1997) mapped the genes for cybL (SDHC; 602413) and cybS (SDHD) to 1q21 and 11q23, respectively, by fluorescence in situ hybridization.
Pseudogenes
Aguiar et al. (2001) confirmed a sequence highly homologous to SDHD cDNA on chromosome 1p36-p34, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of their samples that was also present in the germline. This sequence did not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of LOH in pheochromocytomas.
SDH Complex Function
In mammalian cells, Spinelli et al. (2021) found that when oxygen reduction is impeded, mitochondrial complex I and dihydroorotate dehydrogenase (DHODH; 126064) can still deposit electrons into the electron transport chain because the accumulation of ubiquinol drives the succinate dehydrogenase complex in reverse to enable electron deposition onto fumarate. Fumarate sustains DHODH and complex I activities by acting as the terminal electron acceptor, maintaining mitochondrial function under oxygen limitation.
Pheochromocytoma/Paraganglioma Syndrome 1
In affected members of families with hereditary paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified heterozygous mutations in the SDHD gene (602690.0001-602690.0005), including the Dutch founder mutation (D92Y; 602690.0004). There was no evidence of imprinting; biallelic expression of the SDHD gene was identified in 3 independent fetal brain samples, 1 fetal kidney sample, 2 independent adult brain samples, and adult lymphocytes. The authors suggested that monoallelic expression of SDHD may be confined to the carotid body and other paraganglioma cells, similar to the brain-limited imprinting of UBE3A (601623) in Angelman syndrome (105830). Germline loss-of-function mutations in the paternal alleles and subsequent somatic loss of normal maternal alleles suggested that SDHD functions as a tumor suppressor gene at the cellular level and needs 2 events for inactivation. On the basis of the phenotypic similarity between PGL tumors and the normal carotid body exposed to chronic hypoxia, Baysal et al. (2000) suggested that cybS is a critical component of the oxygen-sensing system of paraganglionic tissue, and that its loss may lead to chronic hypoxic stimulation and cellular proliferation.
In commenting on a case of thoracic pheochromocytoma (paraganglioma) in a 19-year-old man whose father received a diagnosis of hypertension in his 50s, Neumann et al. (2001) pointed to evidence indicating that germline mutations in the VHL gene (608537), causing von Hippel-Lindau disease (193300), and mutations in the SDHD gene together account for 15 to 20% of all nonfamilial presentations of pheochromocytoma. If the father in the case at hand had a pheochromocytoma-paraganglioma syndrome, then the likelihood of finding a germline mutation in SDHD or VHL rises higher than 20%.
Gimm et al. (2000) identified several mutations in the SDHD gene in unrelated patients. One patient had a pheochromocytoma and a carotid body paraganglioma (see 602690.0010); 2 unrelated patients had the same mutation (602690.0011), 1 with an extraadrenal intraabdominal pheochromocytoma with involvement of the jugular fossa, suggesting malignancy, and 1 with an isolated intestinal lipoma; and a 33-year-old woman had 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic (see 602690.0002). Finally, the authors identified a somatic SDHD mutation in a pheochromocytoma (602690.0003). The results indicated that SDHD plays a role in the pathogenesis of pheochromocytoma.
Badenhop et al. (2001) studied 4 families with familial carotid body paragangliomas, 2 of which exhibited coinheritance of PGL and sensorineural hearing loss or tinnitus. Sequence analysis identified mutations in exon 1 and exon 3 of the SDHD gene (602690.0003; 602690.0013; 602690.0014; 602690.0015). The PGL1 region contains another gene, DPP2/TIMM8B (606659), a homolog of the X-linked TIMM8A gene (300356), mutations in which cause dystonia and deafness seen in Mohr-Tranebjaerg syndrome (304700). The authors found no base changes in the TIMM8B gene and concluded that the association of paraganglioma with sensorineural hearing loss could not be explained by the proximity of the TIMM8B and SDHD genes. Badenhop et al. (2001) found no apparent loss of heterozygosity at the site of the SDHD mutations in the paraganglioma tumors. However, RT-PCR analysis of tumor samples showed monoallelic expression of the mutant (paternal) allele as expected for imprinting. Thus the inheritance and expression of the SDHD gene is consistent with the PGL1 gene being subject to genomic imprinting.
Taschner et al. (2001) found that 2 founder mutations, asp92 to tyr (602690.0004) and leu139 to pro (602690.0016), were responsible for paragangliomas in 24 and 6 of 32 independently ascertained Dutch paraganglioma families, respectively. These 2 mutations were detected among 20 of 55 isolated patients as well. Ten of the isolated patients had multiple paragangliomas, and in 8 of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, Taschner et al. (2001) demonstrated that the maternally derived wildtype SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene.
Cascon et al. (2002) performed sequence analysis of the 4 exons of the SDHD gene in 25 consecutive, unrelated patients with pheochromocytoma and/or paraganglioma. There were 18 patients with pheochromocytoma, 4 with paraganglioma alone, and 3 with both, who had tested negative for germline mutations in the VHL (608537) and RET (164761) genes. They detected 5 heterozygous germline sequence variants: 2 missense mutations also found in control chromosomes, G12S (602690.0011) and H50R (602690.0019); a silent mutation (S68S) considered to be a polymorphism; and 2 novel truncating mutations. (The H50R and G12S mutations were later reclassified as variants of unknown significance.) The 2 truncating mutations were a 4-bp frameshift deletion in exon 4 (602690.0022) in an apparently sporadic case of paraganglioma and pheochromocytoma, and a nonsense mutation in exon 2 (602690.0023) in a patient with paraganglioma and a family history of pheochromocytoma.
In 11 (4%) of 271 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified 7 different germline mutations in the SDHD gene (see, e.g., 602690.0002; 602690.0004; 602690.0025; 602690.0026).
Riemann et al. (2004) provided a tabulation of known mutations in the SDHD gene causing paraganglioma. They noted that in addition to mutation in the SDHD gene, loss of heterozygosity (LOH) on chromosome 11, mainly in 11q23, had been observed in paragangliomas (Devilee et al., 1994; van Schothorst et al., 1998).
Hensen et al. (2004) demonstrated exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and pheochromocytomas, suggesting that combined loss of the wildtype SDHD allele and maternal 11p region is essential for tumorigenesis. They hypothesized that this is driven by selective loss of 1 or more imprinted genes in the 11p15 region. In paternally but not maternally derived SDHD mutation carriers, this can be achieved by a single event: nondisjunctional loss of the maternal chromosome 11. Hensen et al. (2004) concluded that the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD.
McWhinney et al. (2004) reported a 3-generation family with 6 affected members with paraganglioma who carried a germline 96-kb deletion (602690.0024) spanning the entire SDHD gene. The family was initially designated mutation-negative for all the PC/PGL-associated genes after PCR-based analysis; fine structure genotyping and semiquantitative duplex PCR analysis were used to detect the whole-gene deletion.
In northern Spain, where cervical paraganglioma is particularly frequent, Lima et al. (2007) screened 48 patients for mutations in the SDHB, SDHC, and SDHD genes. Eight sporadic cases (22.2%) carried pathogenic germline mutations, 6 of which were in SDHB and 2 in SDHD. Three families had mutations in SDHD and 1 in SDHB. SDHD mutations were primarily frameshift.
Paraganglioma and Gastric Stromal Sarcoma
In a male patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a germline 1-bp heterozygous deletion in the SDHD gene (602690.0027). In 5 other families with the dyad, the authors also found germline mutations in the SDHB (see, e.g., 185470.0012 and 185470.0013) and SDHC (602413.0004) genes, respectively. None of the patients had mutations in the KIT (164920) or PDGFRA (173490) genes, which have been associated with gastrointestinal tumors.
C Cell Hyperplasia and Hypercalcitoninemia
Lima et al. (2003) reported a family with C cell hyperplasia and hypercalcitoninemia in which no cases of medullary carcinoma had occurred and which lacked an identifiable causative RET mutation. Four of the family members showed hypercalcitoninemia, and marked C cell hyperplasia was present in each of the 3 in whom thyroidectomy had been performed. A germline mutation in exon 2 of the SDHD gene (149A-G) was found in 6 members of the family; all the 4 available members with hypercalcitoninemia possessed the mutation. One of the 5 available members without hypercalcitoninemia, an 18-year-old female, also showed the mutation. The mutation was also identified in 11 of 474 control chromosomes (2.3%), which caused the authors to question whether the mutation is particularly prevalent in the Portuguese population or is regularly associated with C cell hyperplasia. Lima et al. (2003) noted that other studies of normal individuals did not find this mutation (Kytola et al., 2002).
Mitochondrial Complex II Deficiency, Nuclear Type 3
In a patient with mitochondrial complex II deficiency nuclear type 3 (MC2DN3; 619167), Jackson et al. (2014) identified compound heterozygous mutations in the SDHD gene (E69K, 602690.0029 and X164L, 602690.0030).
Alston et al. (2015) identified a homozygous missense mutation in the SDHD gene (D92G; 602690.0031) in an infant with MC2DN3 who died of cardiac failure and left ventricular noncompaction on the first day of life.
Associations Pending Confirmation
For discussion of a possible association between Cowden syndrome (see 158350) and variation in the SDHD gene, see 602690.0011, 602690.0019, and 602690.0028.
For discussion of a possible association between intestinal carcinoid tumors (see 114900) and Merkel cell carcinomas and variation in the SDHD gene, see 602690.0011 and 602690.0019.
Aguiar et al. (2001) sequenced the entire coding region of the SDHD genes from a series of pheochromocytomas (see 171300). Although they did not find mutations, they identified a new intronic SNP (97739A-G) in 15% of the samples.
In a family with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a glu36-to-ter (E36X) mutation within the mitochondrial signal peptide.
In a family with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in an arg38-to-ter (R38X) substitution within the mitochondrial signal peptide.
Gimm et al. (2000) identified the R38X mutation in a 33-year-old woman with 2 extraadrenal pheochromocytomas, 1 intraabdominal and 1 intrathoracic.
In the germlines of 2 unrelated patients with sporadic pheochromocytomas, Neumann et al. (2002) identified the R38X substitution, resulting from a 112C-T transition in exon 2 of the SDHD gene. The mutation was not identified in 600 control chromosomes.
In 5 families with autosomal dominant paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous C-to-T transition in the SDHD gene, resulting in a pro81-to-leu (P81L) substitution. The proline at position 81 is conserved in human, Bos taurus, Ascaris, and Caenorhabditis elegans.
Milunsky et al. (2001) found the P81L mutation in 3 of 7 families with hereditary paraganglioma. Since this mutation results in the elimination of a normally occurring restriction endonuclease site (MspI), Milunsky et al. (2001) developed a restriction enzyme assay to screen for this mutation.
Badenhop et al. (2001) found the P81L mutation in an individual with paraganglioma who developed sensorineural hearing loss. The mutation was also found in 3 other family members who had only paraganglioma.
In an analysis of 23 families with paragangliomas, Astrom et al. (2003) identified the P81L mutation in 14 (approximately 61%). P81L had been implicated both as a founder and as a recurrent mutation among U.S. families (Baysal et al., 2002). Haplotype analyses of the 14 P81L carrier families indicated that 5 lacked the founder haplotype, suggesting independent origin.
Pheochromocytoma, Somatic
Gimm et al. (2000) found the P81L mutation in the heterozygous state as a somatic mutation in tumor tissue from a patient with sporadic (nonfamilial) pheochromocytoma (see 171300). Flanking markers also showed loss of heterozygosity.
Baysal et al. (2000) identified a Dutch founder mutation in hereditary paraganglioma (PPGL1; 168000), a heterozygous G-to-T transversion in the SDHD gene, resulting in an asp92-to-tyr (D92Y) substitution. This residue is conserved in 4 eukaryotic multicellular organisms, including human.
Neumann et al. (2002) identified the D92Y mutation in the germline of a patient with sporadic pheochromocytoma. The D92Y substitution resulted from a 274G-T transversion in exon 3 of the SDHD gene. The mutation was not identified in 600 control chromosomes.
Hensen et al. (2012) identified the D92Y mutation in almost 70% of Dutch paraganglioma/pheochromocytoma patients with a mutation in a succinate dehydrogenase gene. The dominance of SDHD mutations was unique to the Netherlands, contrasting with the higher prevalence of SDHB (185470) mutations found elsewhere.
In affected members of a family with hereditary paraganglioma (PPGL1; 168000), Baysal et al. (2000) identified a heterozygous A-to-T transversion in the SDHD gene, resulting in a his102-to-leu (H102L) substitution. In the E. coli enzyme, his102 is located in a region thought to harbor an axial ligand for heme.
In affected members of an Italian family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a 1-bp insertion (13732insT) in exon 4 of the SDHD gene, leading to a frameshift and truncated protein.
In affected members of a German family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a heterozygous missense mutation in exon 4 of the SDHD gene, resulting in a tyr114-to-cys (Y114C) substitution. This nonconservative amino acid substitution could alter the conformation of the protein.
In affected members of an English family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a heterozygous mutation in exon 2 of the SDHD gene, resulting in a ser32-to-ter (S32X) substitution.
In affected members of a German family with hereditary paraganglioma (PPGL1; 168000), Milunsky et al. (2001) identified a heterozygous 1-bp deletion (13838delG) in exon 4 of the SDHD gene, leading to a frameshift and premature termination of the protein.
In a patient with a carotid body paraganglioma and a pheochromocytoma (PPGL1; 168000), Gimm et al. (2000) identified a heterozygous splice site mutation in the SDHD gene, IVS1+2T-G. The mutation was not identified in 78 control alleles.
This variant, formerly titled COWDEN SYNDROME 3, with the Included titles of Intestinal Carcinoid Tumors, Paragangliomas-1, Pheochromocytoma, and Somatic Merkel Cell Carcinoma, has been reclassified based on a review of the ExAC database by Hamosh (2018): the G12S variant was present in 881 of 121,216 alleles and in 5 homozygotes, with an allele frequency of 0.007268 (July 11, 2018).
Cowden Syndrome
In 4 unrelated patients with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous G12S substitution in the SDHD gene. This mutation was not identified in 700 control subjects. The G12S mutation was associated with increased manganese superoxide dismutase expression, increased reactive oxygen species, and a 1.9-fold increase in both AKT and MAPK expression. All 4 patients were women, ranging in age from 42 to 69 years. Three of 4 manifested breast cancer; 1 had thyroid cancer; 1 had renal cancer; 1 had uterine cancer; and 3 had uterine leiomyomas.
Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling.
Pheochromocytoma/Paraganglioma Syndrome 1
In a patient with an extraadrenal intraabdominal pheochromocytoma (PPGL1; 168000), Gimm et al. (2000) identified a gly12-to-ser (G12S) substitution in the SDHD gene. There was involvement of the jugular fossa, suggesting malignancy, An unrelated patient with an intestinal lipoma had the same mutation. The G12S substitution was identified in 1.3% of control chromosomes, and the authors concluded that it is either a low-penetrance mutation or a rare polymorphism.
In a patient with a caudal equina paraganglioma and cerebellar tumors that had developed 22 years later, Masuoka et al. (2001) identified the G12S substitution. There was no family history of paragangliomas. Twenty-one additional cases of spinal paraganglioma had the wildtype SDHD sequence.
Cascon et al. (2002) identified the G12S and S68S substitutions in a patient with sporadic pheochromocytoma. However, the G12S substitution was identified in 5 (2.5%) of 200 control chromosomes, and Cascon et al. (2002) concluded that G12S is a polymorphism. In addition, the S68S substitution was found in all 5 controls with the G12S substitution, indicating that the 2 substitutions are in linkage disequilibrium.
In a patient with paragangliomas, Perren et al. (2002) identified a heterozygous G12S substitution. Clinical manifestations included a paratracheal paraganglioma, C-cell hyperplasia of the thyroid, and hyperplasia of ACTH-producing cells of the pituitary. There was no family history of the disorder, and the mutation was not identified in 93 controls.
Intestinal Carcinoid Tumors and Merkel Cell Carcinoma
Kytola et al. (2002) identified a 34G-A transition in exon 1 of the SDHD gene, resulting in the G12S substitution, in the primary tumor of a man diagnosed with nonfamilial midgut carcinoid (see 114900) at 71 years of age. The alteration was also present in the constitutional tissue of the patient, confirming its germline origin. Because the G12S variant led to the elimination of a restriction site for BanI, a restriction cleavage assay was applied to confirm the presence of the change in the patient and to exclude its occurrence in 200 normal individuals. The patient also carried a normally occurring silent polymorphism, ser68-to-ser (S68S), which was previously reported by Baysal et al. (2000). The same G12S missense change accompanied by the S68S polymorphism was also observed by Kytola et al. (2002) in a Merkel cell carcinoma tumor. No normal DNA was available to clarify whether the sequence variants occurred somatically or were present in the germline. To determine whether the tumors with G12S/S68S were associated with a common founder haplotype, Kytola et al. (2002) genotyped 4 microsatellites close to and flanking SDHD. The results excluded the existence of a common founder chromosome. The tumor in the patient with midgut carcinoid showed loss of heterozygosity on genotyping with markers D11S5011 and D11S1986.
In affected members of a French family with pheochromocytoma/paraganglioma syndrome-1 (PPGL1; 168000), Gimenez-Roqueplo et al. (2001) identified a heterozygous nonsense mutation (R22X) in the SDHD gene. The father and his elder son had bilateral neck paragangliomas, whereas the second son had a left carotid body paraganglioma and an ectopic mediastinal pheochromocytoma. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor, but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, which was not detected in 6 sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. RT-PCR measurements confirmed that vascular endothelial growth factor (VEGF; 192240) and endothelial PAS domain protein-1 (EPAS1; 603349) mRNA levels were significantly higher than those observed in sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma was associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors. The overexpression of angiogenic factors may stimulate angiogenesis and therefore promote tumor growth. It has been suggested that mitochondria are the primary site of oxygen sensing in the carotid body (Prabhakar, 2000). Gimenez-Roqueplo et al. (2001) noted that several angiogenic markers that may be involved in tissue adaptation to hypoxia had been observed in inherited paragangliomas.
In affected members of a family with familial carotid body paraganglioma associated with sensorineural hearing loss (PPGL1; 168000), Badenhop et al. (2001) identified a heterozygous 2-bp deletion in exon 3 of the SDHD gene, creating a premature stop codon at position 67. They had information on 4 generations. One female with both paraganglioma and deafness/tinnitus had 5 children unaffected on both scores; another female with paraganglioma and hearing loss had 2 unaffected children and 1 child with deafness/tinnitus only. The latter finding was consistent with the fact that only affected males transmitted paraganglioma to their children and that monoallelic expression of the mutant (paternal) allele was observed, as expected for imprinting.
In 5 affected members in 2 generations of a family with paragangliomas (PPGL1; 168000), Badenhop et al. (2001) identified a heterozygous 3-bp deletion in exon 3 of the SDHD gene, resulting in the deletion of tyr93. An affected male transmitted paragangliomas to 2 of his 3 children; an affected female had 2 unaffected children, consistent with genomic imprinting.
In a father and his 2 sons with paragangliomas (PPGL1; 168000), Badenhop et al. (2001) found a heterozygous G-to-C substitution in exon 1 of the SDHD gene, which resulted in change of the initiation methionine codon to isoleucine (M1I). As the next methionine codon in the SDHD gene was not until met91, the met1-to-ile missense mutation was expected to produce a nontranslated transcript.
Taschner et al. (2001) found that a founder mutation in the SDHD gene, resulting in a leu139-to-pro (L139P) substitution, accounted for 6 of 32 independently ascertained Dutch families with paragangliomas (PPGL1; 168000). The L139P mutation was also found in 1 of 55 'isolated' Dutch families.
In a 2-generation family with pheochromocytomas (PPGL1; 168000), Astuti et al. (2001) identified a heterozygous 2-bp deletion in exon 2 of the SDHD gene (6799-6800), resulting in a truncated protein of 66 amino acids (compared with 159 in the wildtype protein). The father, who carried the mutation and was unaffected, had 3 affected children by 1 wife and 1 affected child by the second wife. Of the 4 affected children, 2 had unilateral adrenal pheochromocytomas, 1 had bilateral adrenal pheochromocytomas, and 1 had a paraaortic pheochromocytoma. The paternal grandmother of the children, a presumed carrier, developed 2 carotid body tumors in her sixth decade. Astuti et al. (2001) suggested that germline SDHD mutation analysis should be done in individuals with familial, multiple, or early-onset pheochromocytoma, even if a personal or family history of head and neck paraganglioma is absent.
This variant, formerly titled CARCINOID TUMORS, INTESTINAL, with the Included titles of Pheochromocytoma and Merkel Cell Carcinoma, Somatic, has been reclassified based on a review of the ExAC database by Hamosh (2018): the H50R mutation was present in 791 of 121,406 alleles and in 6 homozygotes, with an allele frequency of 0.006515 (July 11, 2018).
Cascon et al. (2002) identified the H50R substitution in 4 (1.4%) of 280 control chromosomes, suggesting it is a polymorphism.
Carcinoid Tumors and Merkel Cell Carinoma
In a patient with midgut carcinoid (see 114900), Kytola et al. (2002) observed a 149A-G transition in exon 2 of the SDHD gene, resulting in a his50-to-arg (H50R) mutation. They also identified the H50R mutation in a Merkel cell carcinoma. The mutation was found to be present constitutionally in the patient with midgut carcinoid; no normal DNA was available from the patient with Merkel cell carcinoma to determine whether the variant was present in the germline.
Pheochromocytoma
Perren et al. (2002) identified a heterozygous H50R substitution in the SDHD in a patient with a paraadrenal pheochromocytoma (PPGL1; 168000). There was no family history of the disorder, and the mutation was not identified in 93 controls.
Cowden Syndrome
Ni et al. (2008) identified a heterozygous H50R substitution in 2 unrelated patients with a Cowden-like phenotype (see 158350). This mutation was not identified in 700 control subjects. Expression studies showed that this mutation resulted in increased manganese superoxide dismutase activity, increased reactive oxygen species, a 2.0-fold increase in AKT expression and a 1.7-fold in MAPK expression. One subject was a 56-year-old woman; the other subject a 55-year-old man. The woman had breast cancer and thyroid cancer, and the man had thyroid cancer. Both had a family history of breast cancer, and the male had a family history of papillary thyroid carcinoma.
Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling.
In a patient of German descent with sporadic bilateral carotid body paraganglioma (PPGL1; 168000), Leube et al. (2004) identified a heterozygous frameshift mutation, 463delA, in exon 4 of the SDHD gene. The frameshift resulted in an aberrant amino acid sequence from codon 155 onward to a premature stop at codon 167.
In 2 unrelated patients with sporadic carotid body paraganglioma (PPGL1; 168000), Riemann et al. (2004) identified a heterozygous c.1A-G transition in exon 1 of the SDHD gene, resulting in a met1-to-val (M1V) substitution in the initiation codon. LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested. In a third patient, the M1V mutation was found only in the tumor tissue. LOH and FISH analyses demonstrated partial/total monosomy for chromosome 11 in the tumor samples tested, consistent with the 2-hit hypothesis of tumor development. A mutation at the same codon, M1I (602690.0015), had previously been reported in cases of familial paraganglioma.
In an apparently sporadic case of pheochromocytoma and paraganglioma (PPGL1; 168000), Cascon et al. (2002) identified a heterozygous 4-bp frameshift deletion in exon 4 of the SDHD gene (13732delGACT), resulting in a truncated protein of 132 amino acids.
In a patient with paragangliomas and a family history of pheochromocytoma (PPGL1; 168000), Cascon et al. (2002) identified a heterozygous c.129G-A transition in exon 2 of the SDHD gene, resulting in a trp43-to-ter (W43X) substitution and a truncated protein of 43 amino acids.
Pigny et al. (2008) reported a family with maternal transmission of the W43X mutation in the third generation. A boy received the mutation from his mother and developed a glomus tympanicum paraganglioma at 11 years of age. He shared only the 11q23 haplotype with the other affected members of the family. Methylation analysis of the differentially methylated region upstream of the maternally expressed H19 gene, mapped to 11p15, showed that the seventh CTCF binding site was hypermethylated in the germline of the affected boy, suggesting a gain of imprinting. The authors concluded that maternal transmission of a SDHD-linked paraganglioma, even if a rare event, can occur. The authors proposed that children who inherit a pathogenic mutation from their mother should be considered at risk for paraganglioma.
In a 2-generation family (family 4194) with 6 affected individuals with pheochromocytoma and paraganglioma (PPGL1; 168000), McWhinney et al. (2004) identified a germline heterozygous whole-gene deletion of SDHD.
In the germlines of 4 unrelated patients with sporadic pheochromocytoma (PPGL1; 168000) Neumann et al. (2002) identified a heterozygous c.33C-A transversion in exon 1 of the SDHD gene, resulting in a cys11-to-ter (C11X) substitution. The mutation was not identified in 600 control chromosomes.
In the germline of a patient with sporadic pheochromocytoma (PPGL1; 168000), Neumann et al. (2002) identified a heterozygous c.14G-A transition in exon 1 of the SDHD gene, resulting in a trp5-to-ter (W5X) substitution. The mutation was not identified in 600 control chromosomes.
In a male patient with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a heterozygous 1-bp deletion (c.57delG) in the SDHD gene. Pasini et al. (2008) provided further information on this patient. He presented at 19 years of age with melena from a gastrointestinal tumor; at age 21 he had a right carotid body tumor and left adrenal pheochromocytoma, and 1 year later a left glomus jugular tumor was excised. At age 32, he presented with metastatic paraganglioma. The mutation was predicted to cause a frameshift and a premature stop codon at position 85.
This variant, formerly titled COWDEN SYNDROME 3, has been reclassified because its contribution to Cowden syndrome (see 158350) has not been confirmed.
In a woman with a Cowden-like phenotype, Ni et al. (2008) identified a heterozygous C-to-A transversion in the SDHD gene, resulting in a his145-to-asn (H145N) substitution. This mutation was not identified in 700 control subjects. The mutation was associated with increased expression of manganese superoxide dismutase, normal reactive oxygen species, and no change in AKT expression but a 1.2-fold increase of MAPK expression. The patient had breast cancer and renal cancer, but no family history of cancer.
Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling.
In a girl, born of unrelated Swiss parents, with encephalomyopathy and biochemical evidence of isolated mitochondrial complex II deficiency (MC2DN3; 619167), Jackson et al. (2014) identified compound heterozygous mutations in the SDHD gene: a c.205G-A transition in exon 3, resulting in a glu69-to-lys (E69K) substitution at a conserved residue in the first hydrophobic alpha helix, and a c.479G-T transversion in exon 4, predicting a change of the stop codon into a codon for leucine, followed by proline, phenylalanine, and a stop codon (Ter164LeuextTer3; 602690.0030) in the fourth hydrophobic alpha helix. These variants were predicted to cause impaired integration of SDHD into the inner mitochondrial membrane. The variants were not found in 200 control individuals, and each unaffected parent was heterozygous for one of the mutations.
For discussion of the ter164-to-leu (X164L) mutation in the SDHD gene that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 3 (MC2DN3; 619167) by Jackson et al. (2014), see 602690.0029.
In an infant, born of unrelated Irish parents, with fatal hypertrophic cardiomyopathy due to mitochondrial complex II deficiency nuclear type 3 (MC2DN3; 619167), Alston et al. (2015) identified a homozygous c.275A-G transition (c.275A-G, NM_003002.3) in the SDHD gene, resulting in an asp92-to-gly (D92G) substitution at a highly conserved residue. Each unaffected parent was heterozygous for the mutation, which was not found in the Exome Sequencing Project (ESP6500) database. Patient skeletal muscle sample showed isolated complex II deficiency (30% residual activity), as well as a significant decrease in the SDHD protein and a decrease in fully assembled complex II. Complementation studies in yeast deficient in the homologous SDH4 gene showed that the mutation was unable to rescue the oxidative growth defect, consistent with a loss of function. Mutation at the same codon (D92Y; 602690.0004) has been identified as a founder mutation in the Dutch population and causative of paraganglioma (PGL1; 168000); yeast studies showed that the D92Y mutation did not affect oxidative growth and caused a milder reduction of SDHD activity compared to D92G.
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