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Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families

Oncogene volume 23, pages 4076–4083 (2004)Cite this article

Abstract

Germline mutations in succinate dehydrogenase subunits B, C and D (SDHB, SDHC and SDHD), genes encoding subunits of mitochondrial complex II, cause hereditary paragangliomas and phaeochromocytomas. In SDHB (1p36)- and SDHC (1q21)-linked families, disease inheritance is autosomal dominant. In SDHD (11q23)-linked families, the disease phenotype is expressed only upon paternal transmission of the mutation, consistent with maternal imprinting. However, SDHD shows biallelic expression in brain, kidney and lymphoid tissues (Baysal et al., 2000). Moreover, consistent loss of the wild-type (wt) maternal allele in SDHD-linked tumours suggests expression of the maternal SDHD allele in normal paraganglia. Here we demonstrate exclusive loss of the entire maternal chromosome 11 in SDHD-linked paragangliomas and phaeochromocytomas, suggesting that combined loss of the wt SDHD allele and maternal 11p region is essential for tumorigenesis. We hypothesize that this is driven by selective loss of one or more imprinted genes in the 11p15 region. In paternally, but not in maternally derived SDHD mutation carriers, this can be achieved by a single event, that is, non-disjunctional loss of the maternal chromosome 11. Thus, the exclusive paternal transmission of the disease can be explained by a somatic genetic mechanism targeting both the SDHD gene on 11q23 and a paternally imprinted gene on 11p15.5, rather than imprinting of SDHD.

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Acknowledgements

We thank CJ Haven for help with the FISH experiments and NJ Kuipers-Dijkshoorn for technical assistance. We acknowledge T van Wezel and M Lombaerts for helpful comments on the manuscript. This research was supported by a grant from the JANIVO foundation.

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Authors and Affiliations

  1. Department of Otolaryngology and Head and Neck Surgery, Leiden University Medical Centre, Albinusdreef 2, H4Q, Leiden, 2333 ZA, The Netherlands

    Erik F Hensen & Andel G L van der Mey

  2. Department of Pathology, Leiden University Medical Center, Albinusdreef 2, L1Q, Leiden, 2333 ZA, The Netherlands

    Erik F Hensen, Ekaterina S Jordanova, Pancras C W Hogendoorn, Peter Devilee & Cees J Cornelisse

  3. Department of Human Genetics, Wassenaarseweg 72, 2333 AL, Leiden University Medical Center, Leiden, The Netherlands

    Ivonne J H M van Minderhout, Peter E M Taschner & Peter Devilee

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  1. Erik F Hensen
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  2. Ekaterina S Jordanova
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Correspondence to Cees J Cornelisse.

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Hensen, E., Jordanova, E., van Minderhout, I. et al. Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families. Oncogene 23, 4076–4083 (2004). https://doi.org/10.1038/sj.onc.1207591

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