SDHD Mutation Carriers Research Articles

Genomic imprinting and environment in hereditary paraganglioma.

Hereditary paraganglioma (PGL) is characterized by the development of slow-growing and vascularized tumors in the paraganglionic system. PGL is caused by germ line heterozygous inactivating mutations in the SDHB (PGL4), SDHC (PGL3), or SDHD (PGL1) genes, which encode three of the four subunits of mitochondrial complex II (succinate dehydrogenase; SDH). Common tumor sites include the carotid body in the neck and paraganglia in the abdomen. The risk of tumor development associated with SDHD mutations is determined by the sex of the transmitting parent, because only a paternal transmission leads to tumorigenesis in the progeny. This transmission pattern suggests operation of genomic imprinting on the SDHD gene. There is also evidence that the risk of tumor development increases at higher altitudes among SDHD mutation carriers. Accordingly, the increased prevalence of SDHD mutations in the Netherlands, attributable to multiple founder mutations, has been explained in part by the low altitudes in this country, which presumably reduce gene penetrance and relax the natural selection. Thus, PGL caused by SDHD mutations represents an unusual example of an inherited monogenic tumor syndrome because the risk of tumorigenesis shows an absolute dependence on the sex of the transmitting parent and may be modified by a ubiquitous environmental factor.

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

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.