LETTER TO JMG An Alu-mediated partial SDHC deletion causes familial and sporadic paraganglioma

H ereditary paraganglioma (PGL) is characterised by slow growing, vascular tumours that can develop in any component of the paraganglia, a neuro-ectodermal system that is distributed from the skull base to the pelvic floor. Common tumour sites include the carotid body in the head and neck and adrenal and extra-adrenal paraganglia in the abdomen. Heterozygous germline inactivating mutations in SDHD, SDHC, and SDHB, which encode three of the four subunits of mitochondrial complex II (succinate dehydrogenase), cause hereditary paraganglioma types 1, 3, and 4 (PGL1, PGL3, and PGL4), respectively. Mutations in the fourth subunit of mitochondrial complex II, SDHA, have yet to be demonstrated in hereditary paraganglioma. Germline loss of function mutations followed by somatic loss of nonmutant alleles in the tumours suggests a tumour suppressor role for mitochondrial complex II in the paraganglia. Over 25 mutations in SDHD and 25 mutations in SDHB have been detected in hereditary paraganglioma, including those reviewed by Baysal and the more recent additions of multiple mutations in SDHB and SDHD. All reported mutations are single nucleotide alterations leading to splice site, missense, nonsense, or frameshift mutations, or intraexonic deletions and insertions of up to four nucleotides, which have been detected through exonic PCR amplifications and sequencing. In contrast to the abundance mutations in SDHB and SDHD, only a single multiply affected family and an isolated case, containing a single nucleotide initiation codon and a splice site mutations in SDHC, respectively, have been described by Niemann et al. 10 However, analyses of SDHC in four series of patients with paraganglioma or pheochromocytoma 6 8 11 12 yielded no definitive SDHC mutations. These findings indicate that the relative contribution of complex II subunit mutations to hereditary paraganglioma is not similar and may reflect currently unrecognised aspects of complex II biology. Hence, it is of utmost importance that role of SDHC in familial and sporadic paragangliomas be confirmed independently. Penetrance of complex II mutations shows peculiar characteristics. Mutations in SDHD cause PGL1 only if the transmission occurs paternally, whereas maternal transmission does not cause disease, suggesting operation of genomic imprinting on SDHD. In contrast, SDHB mutations are transmitted both paternally and maternally. Thus far, transmissions of SDHC mutations causing disease occurred through mothers in the one multiplex family and in one isolated case. Because the molecular basis of the parent of origin effects in PGL1 is unknown, it is unclear whether transmissions of mutations in SDHC, the protein product of which couples with that of SDHD and forms the membrane spanning domain of mitochondrial complex II, also shows any parent of origin effects.