Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD

Eur J Hum Genet. 2008 Jan;16(1):79-88. doi: 10.1038/sj.ejhg.5201904. Epub 2007 Aug 1.


Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Antineoplastic Agents / therapeutic use
  • Base Sequence
  • Benzamides
  • Child
  • DNA Primers / genetics
  • DNA, Neoplasm / genetics
  • Female
  • Gastrointestinal Stromal Tumors / drug therapy
  • Gastrointestinal Stromal Tumors / enzymology*
  • Gastrointestinal Stromal Tumors / genetics*
  • Gastrointestinal Stromal Tumors / pathology
  • Genes, Dominant
  • Germ-Line Mutation*
  • Heterozygote
  • Humans
  • Imatinib Mesylate
  • Iron-Sulfur Proteins / genetics*
  • Loss of Heterozygosity
  • Male
  • Membrane Proteins / genetics*
  • Neoplastic Syndromes, Hereditary / drug therapy
  • Neoplastic Syndromes, Hereditary / enzymology*
  • Neoplastic Syndromes, Hereditary / genetics*
  • Neoplastic Syndromes, Hereditary / pathology
  • Paraganglioma / drug therapy
  • Paraganglioma / enzymology*
  • Paraganglioma / genetics*
  • Paraganglioma / pathology
  • Piperazines / therapeutic use
  • Pyrimidines / therapeutic use
  • Succinate Dehydrogenase / genetics*


  • Antineoplastic Agents
  • Benzamides
  • DNA Primers
  • DNA, Neoplasm
  • Iron-Sulfur Proteins
  • Membrane Proteins
  • Piperazines
  • Pyrimidines
  • SDHC protein, human
  • SDHD protein, human
  • Imatinib Mesylate
  • SDHB protein, human
  • Succinate Dehydrogenase