Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas

Abstract

Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.

Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome

“…In particular, loss of chromosome 1p is important for both MEN 2-related and sporadic tumors but not the VHL-related pheochromocytomas. These ®ndings are consistent with a recent report by Benn et al (2000), who found loss of 1p in 61% of sporadic pheochromocytomas and 80% of MEN2-related pheochromocytomas but none of the two VHL-related pheochromocyotmas. It will be interesting to conduct a large study to correlate the clinical parameters of these various types of pheochromocytomas with these genetic alterations.…”

No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma

“…Using DGGE and sequencing, we detected seven different germline nucleic acid changes. The intronic sequence variants ivs2+33A>G and ivs2+35G>A are known polymorphisms (Benn et al 2003) with a reported allelic frequency of 4% and 12% respectively (Benn et al 2003). We detected an almost identical frequency of these polymorphisms in sporadic and familial MTC patients as well as in our control individuals (Table 2).…”

Increased urinary dopamine excretion in association with bilateral carotid body tumours - clinical, biochemical and genetic findings

“…16 In contrast, both maternal and paternal inheritance of SDHB mutations has been reported. 17 The mutation in the SDHB gene reported for our patient,724C4T (Arg242Cys), has been previously reported for a female patient with a unilateral glomus vagale tumour and no family history, but the pathogenicity of this mutation has not yet been established. 18 It is possible that this variant could be a normal polymorphism of the gene, although subunits SDHA and SDHB of succinate dehydrogenase (mitochondrial complex II) form the hydrophilic catalytic part of the complex and are highly conserved.…”