Alternative titles; symbols
HGNC Approved Gene Symbol: SDHB
SNOMEDCT: 1187383001, 128755003, 420120006, 722377004; ICD10CM: C49.A;
Cytogenetic location: 1p36.13 Genomic coordinates (GRCh38) : 1:17,018,722-17,054,032 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.13 | Gastrointestinal stromal tumor | 606764 | Autosomal dominant; Isolated cases | 3 |
| Mitochondrial complex II deficiency, nuclear type 4 | 619224 | Autosomal recessive | 3 | |
| Paraganglioma and gastric stromal sarcoma | 606864 | 3 | ||
| Pheochromocytoma/paraganglioma syndrome 4 | 115310 | Autosomal dominant | 3 |
Complex II in mitochondria, of which succinate dehydrogenase (EC 1.3.99.1) is a component, has 4 subunits. In order of decreasing molecular mass, they are the flavoprotein (SDHA; 600857), the iron-sulfur protein (SDHB), and the 2 integral membrane proteins, SDHC (602413) and SDHD (602690) (summary by Kita et al., 1990).
Kita et al. (1990) cloned and sequenced the iron-sulfur protein subunit. A clone was isolated from a human liver cDNA library. The open reading frame encodes a 252-amino acid protein. The amino acid sequence showed approximately 94% homology with that of bovine heart. Au et al. (1995) described the complete genomic clone for the gene encoding the iron-sulfur protein subunit.
Au et al. (1995) determined that the entire SDHB transcript is encoded by 8 exons within approximately 40 kb.
Leckschat et al. (1993) used a partial human cDNA clone corresponding to the iron protein subunit of succinate dehydrogenase in Southern analyses of restriction enzyme digests of genomic human and hamster DNA, as well as hamster-human hybrids containing a limited number of human chromosomes, to demonstrate that the gene is located on human chromosome 1. Using the same genomic clone, they subregionalized the gene to 1p36.1-p35 by fluorescence in situ hybridization.
Mascarello et al. (1980) described an SDH-deficient hamster cell line that was complemented by human chromosome 1. It was presumed that, because it mapped to chromosome 1, the iron-sulfur protein subunit gene complemented the deficiency in the mutant. Oostveen et al. (1995) found that in fact it was protein from the bovine SDH3 gene (corresponding to human SDHC and encoding 1 of the 2 integral membrane proteins) that complemented the hamster mutation. Thus there are 2 SDH genes on chromosome 1.
Pollard et al. (2005) stated that the nuclear-encoded Krebs cycle enzymes fumarate hydratase (FH; 136850) and succinate dehydrogenases like SDHB act as tumor suppressors, and germline mutations in these genes predispose individuals to leiomyomas and renal cancer (HLRCC; 150800) and to paragangliomas, respectively. Pollard et al. (2005) showed that FH-deficient cells and tumors accumulated fumarate and, to a lesser extent, succinate. SDH-deficient tumors principally accumulated succinate. In situ analysis showed that these tumors also overexpressed HIF1A (603348), activation of HIF1A targets like VEGF (192240), and high microvessel density. Pollard et al. (2005) hypothesized that increased succinate and/or fumarate may stabilize HIF1A, and that the basic mechanism of tumorigenesis in paraganglioma and leiomyomas and renal cancer may be pseudohypoxic drive, just as it is in von Hippel-Lindau syndrome (193300).
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 4
In affected members of families with paragangliomas (PPGL4; 115310), Astuti et al. (2001) identified mutations in the SDHB gene (185470.0001-185470.0002). Clinical manifestations included pheochromocytomas, extraadrenal pheochromocytomas, and paragangliomas. A mutation in the SDHB gene (185470.0003) was also identified in the blood and tumor tissue of 1 of 24 cases of sporadic pheochromocytoma. The findings extended the link between mitochondrial dysfunction and tumorigenesis, and suggested that germline SDHB mutations are an important cause of pheochromocytoma susceptibility.
Young et al. (2002) identified a mutation in the SDHB gene (185470.0004) in a man and his son, both of whom had malignant catecholamine-secreting paragangliomas.
Gimenez-Roqueplo et al. (2002) reported a case of a malignant sporadic pheochromocytoma (see 171300) induced by a germline missense mutation in the SDHB gene. Within the tumor, loss of heterozygosity (LOH) at chromosome 1pter led to a null SDHB allele and to a complete loss of complex II enzymatic activity. In situ hybridization and immunohistochemistry experiments showed a high expression of hypoxic-angiogenic responsive genes, similar to that previously observed in inherited SDHD tumors. The authors concluded that the complex II mitochondrial genes play a role in the oxygen-sensing pathway and in the regulation of angiogenesis of neural crest-derived tumors.
In 12 (4%) of 271 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified 9 different germline mutations in the SDHB gene (see, e.g., 185470.0004-185470.0006; 185470.0008; 185470.0009).
Vanharanta et al. (2004) identified 2 families in which renal cell carcinoma (RCC; see 144700) occurred in patients carrying SDHB mutations (185470.0005; 185470.0006). In 1 family, both patients with RCC had paragangliomas; in another family, the mother of the patient with RCC had a paraganglioma. Tumor tissues from the RCCs showed loss of the remaining wildtype allele. The authors concluded that germline SDHB mutations can predispose to early-onset kidney cancers in addition to paragangliomas.
Cascon et al. (2006) investigated the frequency of gross SDH deletions in 24 patients who tested negative for point mutations and had at least 1 of the recommended features for genetic testing. For this purpose, they used a technique to specifically detect gross deletions affecting SDHB, SDHC (602413), and SDHD (602690). They identified 3 heterozygous SDHB deletions in 3 independent cases with paraganglioma: 1 whole SDHB deletion and 2 deletions exclusively affecting exon 1 of 15.69 kb and 20.3 kb (185470.0017 and 185470.0018, respectively). These latter mutations matched the unique gross deletion of SDHB exon 1 previously reported by McWhinney et al. (2004); see 185470.0007. Thus, the region of exon 1 could be a hotspot for SDHB deletions. These alterations can account for a considerable number of both familial and apparently sporadic paraganglioma cases.
Brouwers et al. (2006) studied the prevalence of germline SDHB mutations in a series of patients with malignant paraganglioma. Pathogenic SDHB mutations were found in 13 of 44 patients (30%). Close to one-third of patients had metastases originating from an adrenal primary tumor, compared with a little over two-thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%. The authors concluded that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas.
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; 7 of 11 different pathogenic mutations (64%) affected SDHB. Ten mutations were novel. Missense mutations were primarily found in SDHB and frameshift mutations in SDHD. The authors concluded that a significant proportion of sporadic cervical PGLs arise as a consequence of intrinsic genetic factors. In patients with germline SDHB mutations, they found no evidence for distant metastases or extraparaganglial malignancies after 7 years' follow-up. Lima et al. (2007) concluded that occult familial cases and familial cases with a proven disease history have a common clinicopathologic signature that distinguishes them from truly sporadic cervical paraganglioma patients without germline mutations.
Paraganglioma and Gastric Stromal Sarcoma
In 3 families with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified 3 different germline mutations in the SDHB gene (see, e.g., 185470.0012 and 185470.0013). In 3 other families with the dyad, the authors also found germline mutations in the SDHC (see, e.g., 602413.0004) and SDHD (602690.0027) genes, respectively. None of the patients had mutations in the KIT (164920) or PDGFRA (173490) genes, which have been associated with gastrointestinal tumors.
Pasini et al. (2008) provided further clinical and molecular information on patients originally reported by McWhinney et al. (2007) (see 185470.0012-185470.0013). DNA analysis of tumors from patients with germline mutations in SDHB and SDHC showed loss of heterozygosity in all samples available for study, suggesting that the gene defects act in a recessive manner.
Gastrointestinal Stromal Tumors
Janeway et al. (2011) identified 3 germline mutations in the SDHB gene (see, e.g., 185470.0004) in 3 different patients with sporadic occurrence of gastrointestinal stromal tumor (GIST; 606764). The patients were 18, 22, and 21 years old, respectively, and none had a personal or family history of paragangliomas. Tumor tissue available from 2 of these patients showed lack of SDHB immunostaining. A fourth patient, who was 16 years old, carried a germline mutation in the SDHC gene (602413.0004). Overall, mutations in these genes accounted for 4 (12%) of 34 patients with isolated GIST lacking KIT (164920) or PDFGRA (173490) mutations. Janeway et al. (2011) evaluated SDHB (185470) expression in 30 GISTs lacking KIT or PDGFRA mutations, 25 of which were also negative for associated SDH mutations confirmed by sequence analysis. Immunohistochemical studies showed lack of SDHB staining in 18 (100%) of 18 pediatric tumors, regardless of SDH mutation status, and in 8 (67%) of 12 adult tumors and weak expression in 4 (33%) of 12 adult tumors. By comparison, only 1 (6%) of 18 KIT-mutant GISTs and 0 of 5 NF1-associated GISTs lacked SDHB expression. These findings implicated a defect in respiration in the pathogenesis of some GIST tumors.
Mitochondrial Complex II Deficiency, Nuclear Type 4
In an Asian girl, born of consanguineous parents, with neurologic impairment, leukoencephalopathy, and biochemical evidence of mitochondrial complex II deficiency (MC2DN4; 619224), Alston et al. (2012) identified a homozygous missense mutation in the SDHB gene (D48V; 185470.0020). Her unaffected parents were heterozygous for the mutation. Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples.
In a Pakistani girl, born to consanguineous parents, with MC2DN4, Ardissone et al. (2015) identified homozygosity for the previously reported D48V mutation in the SDHB gene. The mutation was found by sequencing of a panel of 7 genes associated with complex II deficiency. A clinically unaffected sib was also homozygous for the mutation. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib. SDHA protein was also reduced in these cells, possibly due to instability of complex II assembly.
In a Turkish boy (patient LD_0756.0A), born of consanguineous parents, with MC2DN4, Vanderver et al. (2016) identified homozygosity for the D48V mutation in the SDHB gene.
In 6 patients with MC2DN4, Helman et al. (2016) identified mutations in the SDHB gene. Five patients had the D48V mutation, 4 (patients 10, 11, 16, and 19) in homozygous state and 1 (patient 15) in compound heterozygous state.
In 2 unrelated children with MC2DN4, Gronborg et al. (2017) identified mutations in the SDHB gene: a Lebanese girl, born of consanguineous parents, was homozygous for a missense mutation (L257V; 185470.0022), and a boy, born of nonconsanguineous parents, was compound heterozygous for D48V and another missense mutation (R230H; 185470.0023). In both patients, SDHB protein content was reduced in patient fibroblasts, muscle fibers showed diffuse and severe lack of SDH staining, and complex II enzyme activity was severely deficient in muscle. The parents of both children were confirmed to be mutation carriers. Gronborg et al. (2017) noted that the R230H mutation was previously reported in heterozygous state in patients with paraganglioma by several authors, including Cerecer-Gil et al. (2010).
In a male infant with MC2DN4, who was born to nonconsanguineous Indian parents, Kaur et al. (2020) identified a homozygous missense mutation in the SDHB gene (A102T; 185470.0024). The parents were heterozygous for the mutation. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.
Associations Pending Confirmation
For discussion of a possible association between Cowden syndrome (see 158350) and variation in the SDHB gene, see 185470.0014 and 185470.0015.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human SDHB is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In affected members of 3 families with pheochromocytoma/paraganglioma syndrome-4 (PPGL4; 115310), Astuti et al. (2001) identified a 402C-T transition in the SDHB gene, resulting in an arg90-to-ter (R90X) substitution. The mutation was predicted to result in a truncated SDHB protein lacking the C-terminal 191 amino acids. One of the families had been reported by Skoldberg et al. (1998). The mutation occurred at a hypermutable CpG dinucleotide; haplotype analysis of the 3 families supported independent origin of the mutations. This mutation was originally published as ARG91TER; the corrected numbering appeared in an erratum.
In a family containing 3 individuals with familial extraadrenal pheochromocytoma and without evidence of cervical paragangliomas (PPGL4; 115310), Astuti et al. (2001) identified a heterozygous 724C-G transversion in exon 6 of the SDHB gene, resulting in a pro197-to-arg (P197R) substitution. This proline is conserved throughout all living species analyzed, from human to rat, Drosophila, yeast, and E. coli. This mutation was originally published as PRO198ARG; the corrected numbering appeared in an erratum.
In a 55-year-old woman with a single sporadic adrenal pheochromocytoma (PPGL4; 115310), Astuti et al. (2001) identified a heterozygous 1-bp deletion (725delC) in exon 6 of the SDHB gene in both blood and tumor tissue. The tumor DNA did not exhibit loss of heterozygosity for markers flanking SDHB. SDHB mutations were not identified in 23 other cases of sporadic pheochromocytomas.
In a man and his son, both of whom had metastatic catecholamine-secreting paragangliomas (PPGL4; 115310), Young et al. (2002) identified a 725G-A transition in exon 7 of the SDHB gene, resulting in an arg242-to-his (R242H) substitution. Sequencing of the SDHB gene in the tumors did not reveal any somatic mutations or loss of heterozygosity of the remaining allele.
Neumann et al. (2002) identified the R242H substitution in the germline of a patient with sporadic pheochromocytoma. The mutation was not identified in 600 control chromosomes.
Janeway et al. (2011) identified a germline R242H mutation in a 21-year-old patient with a sporadic gastrointestinal stromal tumor (GIST; 606764).
Among 16 probands with pheochromocytoma/paragangliomas-4 (PGL4; 115310), Vanharanta et al. (2004) found 1 family with an 847_850delTCTC germline mutation in which 2 members had renal cell carcinoma (see 144700) of solid histology, at ages 24 and 26 years. Both also had paraganglioma. Tumor tissue from the RCCs showed loss of the remaining wildtype allele.
Neumann et al. (2002) identified the 847delTCTC mutation in the germlines of 2 unrelated patients with sporadic pheochromocytoma. The mutation was not identified in 600 control chromosomes.
In a registry of early-onset renal cell carcinomas (see 144700), Vanharanta et al. (2004) found a family in which both a son with clear cell RCC and his mother with a cardiac paraganglioma tumor (PPGL4; 115310) had an arg27-to-ter (R27X) germline mutation in the SDHB gene. Tumor tissue from the RCC showed loss of the remaining wildtype allele.
Neumann et al. (2002) identified the R27X substitution in the germline of patient with sporadic pheochromocytoma. The R27X substitution resulted from a 213C-T transition in exon 2 of the SDHB gene. The mutation was not identified in 600 control chromosomes.
In a Brazilian family with 3 affected members in 2 generations with paragangliomas (PPGL4; 115310), McWhinney et al. (2004) identified an approximately 1.0-kb germline deletion of the 5-prime end of the SDHB gene, including all or part of exon 1. Breakpoints were delineated in the 5-prime UTR and in intron 1 of the SDHB gene. See 185470.0017 and 185470.0018 for additional reports of SDHB exon 1 deletions.
In the germlines of 2 unrelated patients with sporadic pheochromocytoma (PPGL4; 115310), Neumann et al. (2002) identified a 270C-G transversion in exon 2 of the SDHB gene, resulting in an arg46-to-gly (R46G) substitution. The mutation was not identified in 600 control chromosomes.
In the germlines of 2 unrelated patients with sporadic pheochromocytoma (PPGL4; 115310), Neumann et al. (2002) identified a 436G-A transition in exon 4 of the SDHB gene, resulting in a cys101-to-tyr (C101Y) substitution. The mutation was not identified in 600 control chromosomes.
By analysis of the germline DNA from 2 brothers and their mother with malignant extraadrenal abdominal paragangliomas (PPGL4; 115310), Maier-Woelfle et al. (2004) identified heterozygosity for an A-to-C transversion in the SDHB gene, resulting in a his132-to-pro (H132P) substitution. The variant was absent in 160 control chromosomes.
In tumor tissue from a woman with sporadic extraadrenal pheochromocytoma (see 171300) in the bladder wall, van Nederveen et al. (2007) identified a heterozygous 299C-T transition in exon 4 of the SDHB gene, resulting in a ser100-to-phe (S100F) substitution. Comparative genomic hybridization and FISH analysis showed loss of heterozygosity of chromosome 1p in tumor tissue, indicating biallelic inactivation of the SDHB gene. There was absence of SDHB expression in tumor cells, indicating complete loss of SDHB function.
In a mother and son with paraganglioma and gastric stromal sarcoma (606864), McWhinney et al. (2007) identified a germline G-to-T transversion at the splice donor site in intron 1 (IVS1DS+1) of the SDHB gene. Pasini et al. (2008) provided additional information on this family with a G-T transversion at position 72+1 in the SDHB gene. The son presented at 37 years of age with melena due to a gastric stromal sarcoma and on further evaluation was found to have a nonfunctioning periaortic ganglioma. Sequencing of a heterozygous aberrant transcript from his WBCs indicated that the first part of intron 1 was transcribed, resulting in a significantly truncated protein with a stop codon in the middle of exon 2. DNA analysis of a tumor sample showed loss of heterozygosity with only the mutant SDHB sequence present. The patient's mother underwent surgery for a pheochromocytoma at 57 years of age, but DNA was not available for analysis.
In male twin sibs with paraganglioma and gastric stromal sarcoma (606864), previously described by Boccon-Gibod et al. (2004), McWhinney et al. (2007) identified a germline G-C transversion at nucleotide 423+1 in the SDHB gene. Their unaffected mother and an unaffected sister also carried the mutation. Pasini et al. (2008) provided additional information on these monozygotic twins with the IVS4+1G-C mutation. One had surgery at 12 years of age for a nonfunctioning paraganglioma of the organ of Zuckerkandl and the other at 13 years of age for a gastric stromal sarcoma. Analysis of lymphocyte DNA from 1 of the brothers showed that the last 18 codons of exon 4 were spliced out, resulting in a truncated protein. The mother and older sister who carried the mutation had negative examinations for gastric stromal carcinoma and paraganglioma.
This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In a patient with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous C-to-G transversion in the SDHB gene, resulting in an ala3-to-gly (A3G) substitution. The mutation was not identified in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase expression, normal reactive oxygen species, and a 1.2-fold increase in AKT expression and 1.3-fold change in MAPK expression. The patient was a 41-year-old woman with breast cancer and uterine leiomyomas and a family history of endometrial 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.
Hamosh (2018) found that the A3G variant was present in heterozygous state in 426 of 97,714 alleles and in 8 homozygotes, with an allele frequency of 0.00436, in the ExAC database (July 11, 2018).
This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by Hamosh (2018).
In 2 women with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous ser163-to-pro (S163P) substitution in the SDHB gene. This mutation was not found in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase function, increased reactive oxygen species, and a 2.7-fold change in AKT expression and 1.7-fold increase in MAPK expression. The patients, 29 and 54 years old, had thyroid cancer, and both had a family history of breast cancer and 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.
Hamosh (2018) found that the S163P variant was present in heterozygous state in 1,523 of 121,404 alleles and in 21 homozygotes, with an allele frequency of 0.01254, in the ExAC database (July 11, 2018).
In 2 sibs with paragangliomas (PPGL4; 115310), Schimke et al. (2010) identified a heterozygous 418G-T transversion in the SDHB gene, resulting in a val140-to-phe (V140F) substitution. The 55-year-old sister and 49-year-old brother both had paraspinal paragangliomas. The mutation was also found in their unaffected 76-year-old mother, suggesting decreased penetrance or a 'leaky' mutation. The family was of note because a deceased sib had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas reminiscent of pheochromocytoma as a young adult, and renal cell carcinoma as an adult; this patient had been previously reported by Fairchild et al. (1979) as having unique occurrence of these cancers. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Schimke et al. (2010) noted the importance of family history in elucidating the etiology of this inherited disorder.
Cascon et al. (2006) detected a germline deletion affecting SDHB exon 1 in a 30-year-old Portuguese male with a secreting retroperitoneal paraganglioma (PPGL4; 115310) and an uncertain family history. The authors found the same loss of SDHB exon 1 in a 14-year-old female proband from a Spanish family with a history of PGL. The proband was admitted to hospital with hypertension and later diagnosed with catecholamine-secreting PGL of the retroperitoneum. The proband's father was diagnosed at age 48 with PGL of the Zuckerkandl organ, which metastasized to the liver at age 53. Bone metastases were found 4 years later. The brothers of the proband also had high levels of dopamine in their urine. Cascon et al. (2006) detected the germline deletion in all 3 of these relatives of the proband. No deletions affecting the SDHC or SDHD genes were found in any patients. Analysis of the genomic structure of the SDHB gene revealed a high density of Alu repeats within the first intron. The authors suggested that Alu-mediated recombination may account for the observed clustering of a gross deletion hotspot.
Cascon et al. (2008) reported 3 additional families, 2 of Spanish and 1 of French origin, with the SDHB exon 1 deletion. In the first Spanish family, the proband was diagnosed at age 19 with retroperitoneal PGL, and multiple metastases in bone, hypophysis, retroperitoneum, and liver. Her sister was diagnosed with an adrenal neuroblastoma with metastasis at age 5 years of age. The proband in the second Spanish family was diagnosed with abdominal PGL and renal oncocytoma at age 17; both were surgically resected. Ten years later she showed bone metastasis. In the French family, the proband had malignant pheochromocytoma (PCC) at age 27 years and died as a result of the disease. He had a relative with benign PCC, diagnosed at age 30 years. Molecular analysis revealed that same deletion breakpoints in all Spanish families resulting in a 15.69-kb deletion, including the 2 families previously reported by Cascon et al. (2006), and a different breakpoint junction in the French family, resulting in a 20.3-kb deletion (185470.0018). Haplotype analysis indicated a founder effect in the Spanish families for the 15.69-kb deletion. All Spanish patients originally came from a small area in the northwest region of the Iberian peninsula.
Solis et al. (2009) reported a large 5-generation family of Spanish Mexican descent with the same 15.69-kb SDHB founder deletion previously described by Cascon et al. (2006, 2008). Eleven of 41 mutation carriers developed PGL in various locations, including the carotid body, adrenal gland, pelvis, and thorax. Penetrance of the founder deletion was estimated to be 35% by age 40 years.
See 185470.0017 and Cascon et al. (2008).
In 2 unrelated Dutch patients with sporadic occurrence of paragangliomas-4 (PPGL4; 115310), Bayley et al. (2006) identified a heterozygous G-to-A transition in intron 4 of the SDHB gene (423+1G-A). RT-PCR analysis from 1 patient showed that the mutation caused a splice site defect and an in-frame deletion of 18 amino acids. The mutation was not found in 300 control chromosomes. One patient was a 50-year-old man who presented with elevated catecholamine levels and a single jugular paraganglioma, and died at the age of 58 due to complications resulting from tumor recurrence. The second patient was a man who presented at age 55 with a single carotid body tumor that was successfully removed. The tumor from this patient was negative for SDH activity.
Hensen et al. (2012) found the 423+1G-A mutation in 22 patients from 9 Dutch families with paragangliomas, making it the most common mutation in the SDHB gene identified in their cohort of 1,045 patients from 340 families. The findings were consistent with a founder effect.
In an Asian girl, born of consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Alston et al. (2012) identified a homozygous c.143A-T transversion (c.143A-T, NM_003000.2) in exon 2 of the SDHB gene, resulting in an asp48-to-val (D48V) substitution. Her unaffected parents were heterozygous for the mutation. The D48 residue is not conserved between human and yeast, but D48 is conservatively substituted by N42 in the yeast Sdh2 protein (yeast ortholog). Construction of an Sdh2 N42D allele rescued the oxidation growth defect of yeast with a deletion of the Sdh2 gene; the N42D variant showed normal SDH activity. Introduction of an N42V substitution did not impair growth of yeast or oxygen consumption, but did cause decreased SDH activity (about 50% of control). Patient fibroblasts showed decreased amounts of fully assembled complex II and almost complete absence of the SDHB subunit. Complex II activity was also decreased in patient muscle samples.
In a Pakistani girl, born to consanguineous parents, with MC2DN4, Ardissone et al. (2015) identified homozygosity for the D48V mutation in the SDHB gene. The mutation, which was identified by sequencing of a panel of 7 genes associated with complex II deficiency, was confirmed by Sanger sequencing. The parents were confirmed to be carriers, and a clinically unaffected older sib was also homozygous for the mutation. The D48V mutation was observed in ExAC at a low frequency of 0.036% in only South Asian subjects, with no homozygotes reported. SDHB protein expression was reduced in patient fibroblasts and lymphocytes as well as in lymphocytes from the clinically unaffected sib who also homozygous for the mutation.
In a Turkish boy (patient LD_0756.0A) with MC2DN4, who was born of consanguineous parents, Vanderver et al. (2016) identified homozygosity for the D48V mutation in the SDHB gene. The mutation was identified by whole-exome sequencing.
In 5 patients with MC2DN4, Helman et al. (2016) identified the D48V mutation in the SDHB gene. It was present in homozygous state in 4 patients (patients 10, 11, 16, and 19) and in compound heterozygous state in 1 (patient 15).
In a male infant, born on nonconsanguineous parents, with MC2DN4, Gronborg et al. (2017) identified compound heterozygous mutations in the SDHB gene: D48V and a c.689G-A transition resulting in an arg230-to-his (R230H; 185470.0023) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were confirmed to be mutation carriers. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining.
In 9 apparently unrelated Dutch patients with paragangliomas (PPGL4; 115310), Bayley et al. (2009) identified a heterozygous 7.9-kb deletion (c.201-4429_287-933del) including exon 3 of the SDHB gene, predicted to result in a frameshift and premature termination (Cys68HisfsTer21). The deletion was found by multiplex ligation-dependent probe amplification (MLPA) analysis of 126 patients who did not carry point mutations in SDH genes, and all patients had the same breakpoints. Haplotype analysis indicated a founder effect. Only 1 patient had a family history of PGL, 5 patients had no family history, and family information from 3 patients was not available. The patients presented with head and neck PGL, extraadrenal PGL, and pheochromocytoma. Bayley et al. (2009) suggested incomplete penetrance associated with this mutation. Functional studies of the variant and studies of patient cells were not performed.
Rijken et al. (2016) reported a large multigenerational Dutch family with PPGL4 due to the Dutch founder 7.9-kb deletion in the SDGB gene. There were 17 family members who carried the mutation, but only 6 had clinical manifestations; 11 patients were disease-free, indicating incomplete penetrance. The age-dependent penetrance of the mutation in this family was estimated to be 9% at age 50 years.
In a Lebanese girl (patient 1), born to consanguineous parents, with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Gronborg et al. (2017) identified homozygosity for a c.769C-G transversion (c.769C-G, NM_003000.2) in the SDHB gene, resulting in a leu257-to-val (L257V) substitution at a highly conserved site. The mutation, which was found by homozygosity mapping and sequencing of the SDHB gene, was present in heterozygous state in the parents. SDHB protein content was reduced in patient fibroblasts, and muscle fibers showed diffuse and severe lack of SDH staining. The mutation was present in 1 of 121,292 alleles in the ExAC database.
Mitochondrial Complex II Deficiency, Nuclear Type 4
For discussion of the c.689G-A transition (c.689G-A, NM_003000.2) in the SDHB gene, resulting in an arg230-to-his (R230H) substitution, that was found in compound heterozygous state in a patient with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224) by Gronborg et al. (2017), see 185470.0020.
Pheochromocytoma/Paraganglioma Syndrome 4
In 2 patients with head and neck paraganglioms (PPGL4; 115310) from a Mexican family living in Guadalajara, Cerecer-Gil et al. (2010) identified a heterozygous germline c.689G-A transition in the SDHB gene, resulting in an arg230-to-his (R230H) substitution.
In an Indian boy with mitochondrial complex II deficiency nuclear type 4 (MC2DN4; 619224), Kaur et al. (2020) identified a homozygous c.304G-A transition (c.304G-A, NM_003000.2) in the SDHB gene, resulting in an ala102-to-thr (A102T) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in homozygous state in the gnomAD database or in an in-house database of 569 individuals. In silico protein modeling suggested that the A102T substitution caused a gain of a polar contact in the SDHB protein, thus altering protein structure.
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