Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma

Cascón, Alberto; Ruiz‐Llorente, Sergio; Cebrián, Arancha; Tellerı́a, Dolores; Rivero, José Casas; Díez, Juan J.; Lopez-Ibarra, Pablo J; Jaunsolo, Miguel Angel; Benı́tez, Javier; Robledo, Mercedes

doi:10.1038/sj.ejhg.5200829

Cited by 53 publications

(41 citation statements)

References 22 publications

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“…The two tissue samples showing a decreased SDH activity and classified as wt at genetic analysis were found to have SDHD somatic mutations. One of these mutations (p.Asp113MetfsX21) has been previously described by Cascon et al (2002), while the second is a novel mutation (p.Leu7CysfsX7; Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

Rapizzi¹,

Ercolino²,

Canu³

et al. 2012

Endocrine-Related Cancer

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To date, the consequences of succinate dehydrogenase (SDH) impairment on overall mitochondrial functions are still obscure. In this study, we evaluated SDH activity and expression and mitochondrial homeostasis in 57 tissue samples of pheochromocytoma (PHEO)/ paraganglioma (PGL) obtained from patients genotyped for PHEO/PGL susceptibility genes. The resulted SDH activity and content always decreased in SDH-mutated tumors, in one out of two MAX-mutated patients and in four patients resulted wild type (wt) at genetic screening. All these four wt patients were further screened for large deletions in SDH genes, TMEM127 and MAX and resulted wt but two had somatic SDHD mutations. The RT-PCR in the MAX-mutated sample suggests that the decrease in SDH depends on complex instability and not on a reduced SDHB expression. SDH mutations neither alter citrate synthase (CS) activity nor the content of voltage-dependent anion channel (VDAC) while the expression of the mitochondrial complex IV (cytochrome c oxidase (COX)) was found extremely variable in all (mutated and wt) samples suggesting an impairment of mitochondrial cristae in these tumors. In conclusion, tumors from patients with germ line SDH mutations invariably show decreased enzymatic activity and content, but an SDH impairment may also depend on SDH somatic mutations or, seemingly, on MAX mutations. The impaired SDH activity in the two wt tissues suggests mutations in other still unknown susceptibility genes. Finally, the extreme variability in COX expression levels is yet to be explained and this strongly suggests to evaluate other mitochondrial features to better understand the mitochondrial role in the pathogenesis of these tumors.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

Rapizzi¹,

Ercolino²,

Canu³

et al. 2012

Endocrine-Related Cancer

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“…More recently, an L95P mutation has also been detected in nine Dutch subjects from the city of Rotterdam (Dannenberg et al 2002) and one family from Nijmegen (Cremers et al 2002), suggesting the presence of a third Dutch founder mutation. Together, these three studies describe 83 "unrelated" PGL1 families and subjects attributable to three founder mutations in the central and western parts of The Netherlands, in stark contrast to the 25 distinct SDHD mutations (reviewed in Baysal 2002) reported thus far among 43 independent familial and nonfamilial cases from the USA (Baysal et al 2000Milunsky et al 2001), Australia (Badenhop et al, 2001), England (Astuti et al 2001a), Germany/Poland (Neumann et al 2002), France (Gimenez-Roqueplo et al 2001), Spain (Cascon et al 2002), and Belgium (Renard et al 2002). The only PGL1 founder effect suggested outside of The Netherlands is P81L, detected in several US families (Baysal et al 1999).…”

Section: Introductionmentioning

confidence: 94%

Altitude is a phenotypic modifier in hereditary paraganglioma type�1: evidence for an oxygen-sensing defect

et al. 2003

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Hereditary paraganglioma type 1 (PGL1) is characterized by slow-growing and vascularized tumors that often develop in the carotid body (CB) and is caused by mutations in the gene for succinate dehydrogenase D ( SDHD) of mitochondrial complex II. The mechanisms of tumorigenesis and the factors affecting penetrance and expressivity are unknown. Because chronic hypoxic stimulation at high altitudes causes sporadic CB paragangliomas, it has been hypothesized that the SDHD gene product may be involved in oxygen sensing. On this background, we examined genotype-phenotype-environment relationships and tested whether higher altitudes adversely affect the phenotype in PGL1. An analysis of 58 subjects from 23 families revealed that nonsense/splicing mutation carriers developed symptoms 8.5 years earlier than missense mutation carriers ( P<0.012). We also found that subjects who were diagnosed with single tumors at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumors ( P<0.012). Pheochromocytomas developed in six subjects (approximately 10%), five of whom had nonsense mutations ( P=0.052). Subjects with pheochromocytomas also lived at higher average altitudes and were exposed to higher altitude-years than those without them ( P=0.026). To test whether altitude is also associated with the more frequent detection of germ-line founder mutations among sporadic cases in The Netherlands than in the USA ( P=0.00033), we calculated population-weighted elevations of the two countries. We found that the population-weighted elevations were approximately 260 m for the US and 2 m for the central-western Netherlands ( P~0), where three Dutch founder mutations were discovered. This finding suggests that low altitudes in The Netherlands reduce penetrance and relax the natural selection on SDHD mutations. Collectively, these data suggest that higher altitudes and nonsense/splicing mutations are associated with phenotypic severity in PGL1 and support the hypothesis that SDHD mutations impair oxygen sensing.

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“…The mutation had been previously described in an individual from Spain. 6 In family 1, the mutation was identified in the two clinically affected family members but also in four asymptomatic carriers (four males). In family 2, the mutation was detected in the two affected family members and in one asymptomatic carrier (one female).…”

Section: Mutation Analysis Of Sdhdmentioning

confidence: 98%

“…The mutation also had been previously described in one Spanish patient. 6 The mutation was present in the affected family member and in two asymptomatic carriers (two females). The father of the index case was known to have paraganglioma but was not available for appropriate clinical and molecular investigation.…”

Section: Mutation Analysis Of Sdhdmentioning

confidence: 98%

Mutation Analysis of the SDHD Gene in Four Kindreds with Familial Paraganglioma

Velasco¹,

Palomar-Asenjo²,

Gañan³

et al. 2005

Diagnostic Molecular Pathology

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The familial paraganglioma syndrome is an autosomal dominant disorder characterized by the presence of carotid body paragangliomas and, less frequently, paragangliomas of the glomus jugulare, glomus vagale, and adrenal pheochromocytomas. Germline mutations of the genes for succinate dehydrogenase subunits D, B, or C (SDHD, SDHB, SDHC) have been identified in some kindreds with familial paraganglioma. In this study, we report the clinicopathologic features of four different kindreds with familial paraganglioma, which were screened for germline mutations in the SDHD gene. DNA was obtained from tumor and normal tissue, as well as from peripheral blood. Mutation analysis was performed by single-strand conformation polymorphism analysis and DNA sequencing. SDHD germline mutations were detected in the affected family members of the four families, as well as in several asymptomatic carriers. An identical mutation in exon 4 of SDHD (334-337delACTG) was identified in two apparently unrelated kindreds. The third family showed a germline mutation in exon 2 (W43X). The mutations present in these three families had been previously described in Spanish families, suggesting a founder effect. The fourth family exhibited a mutation in exon 2 of SDHD (170-171delTT), which had not been previously identified. The affected family members of the four kindreds showed paragangliomas, located in the head and neck region, and all of them were benign. These results confirm that genetic testing of SDHD may be a powerful tool for the identification of the syndrome in patients with multiple or bilateral paragangliomas.F amilial paraganglioma is a dominantly inherited disorder, characterized by the development of paragangliomas in the head and neck region, occasionally coexisting with adrenal pheochromocytomas. Penetrance of the disease is incomplete and suggests maternal imprinting of the associated genes. 1 Offspring of female carriers do not develop the disease, while 50% of offspring of male carriers do develop the disease.Paragangliomas are tumors originating from paraganglia which are dispersed neuroendocrine organs and are characterized by catecholamine and peptide-producing cells derived from the neural crest. One group of paraganglia is related to the sympathoadrenal and the other to the parasympathetic autonomic nervous system.Germline mutations in the genes coding for the succinate dehydrogenase (SDH) subunits D, B, and C (SDHD, SDHB, SDHC) are found in virtually all familial paraganglioma patients and occasionally in apparently sporadic paraganglioma patients. [2][3][4] The SDH enzyme complex II is involved in the Krebs cycle and the aerobic respiratory chain. Loss of complex II enzymatic activity in paraganglia is associated with a high expression of hypoxic-angiogenic responsive genes such as vascular endothelial growth factor. 5 In this study, we report the clinical and pathologic features of affected family members of four kindreds with familial paraganglioma, as well as the results from mutational analysis of the SDHD gene. In...

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Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma

Cited by 53 publications

References 22 publications

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

Altitude is a phenotypic modifier in hereditary paraganglioma type�1: evidence for an oxygen-sensing defect

Mutation Analysis of the SDHD Gene in Four Kindreds with Familial Paraganglioma

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