J Med Genet 41:703-709 doi:10.1136/jmg.2004.019224
  • Letters to JMG

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

  1. B E Baysal1,2,
  2. J E Willett-Brozick1,
  3. P A A Filho3,
  4. E C Lawrence2,
  5. E N Myers3,
  6. R E Ferrell2
  1. 1Department of Obstetrics, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  2. 2Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
  3. 3Department of Otolaryngology, The University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  1. Correspondence to:
 Dr Bora E Baysal
 Magee-Womens Research Institute, 204 Craft Ave. R332B, Pittsburgh, PA, 15213, USA;
  • Received 25 March 2004
  • Accepted 30 March 2004

Hereditary 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.1 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 non-mutant alleles in the tumours2–4 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 Baysal1 and the more recent additions of multiple mutations in SDHB4–6 and SDHD.7–9 All reported mutations are single nucleotide alterations leading to splice site, missense, nonsense, or frameshift mutations, or intra-exonic 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.3,10 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 …