Authors
Bayley, J.-P., Rebel, H. G., Devilee, P.
Abstract
Genes encoding subunits of the mitochondrial tricarboxylic acid cycle enzyme complex, succinate dehydrogenase (SDH), are the leading cause of the neuroendocrine tumour syndrome hereditary paraganglioma-pheochromocytoma. Pathogenic variants of SDHD and SDHAF2 confer a remarkable parent-of-origin tumour risk, in which paternally-transmitted variants cause tumours but maternally-transmitted variants do not. Formulated to explain this observation, the Hensen hypothesis proposes that loss of an (unknown) imprinted gene(s), together with the remaining wildtype SDH gene, is a prerequisite for tumour formation. This study had three objectives, first, as a test of the Hensen model, second, as a potential model for a disease for which no mouse or cell model currently exists, and finally, as a test of chromosomal configuration to interrogate large genomic regions carrying an unknown phenotypic modifier. We crossed an SDH gene knockout line to a Robertsonian (Rb) chromosome line harbouring the gene imprinting centre implicated in human tumourigenesis, to create a metacentric chromosome with characteristics of human chromosome 11. Distinct phenotypes were noted in various cohorts. In heterozygote Rb mice we noted both weight gain and frequent immune activation. In Sdhc knockout mice with both heterozygous and homozygous Rb chromosomes, thyroid abnormalities, including papillary thyroid carcinoma-like tumours, were common due to apparent synergy between the Sdhc KO and the Rb chromosome. We also found a single case of bilateral pheochromocytoma in which loss of Sdhc was not the driver. Although few studies of Robertsonian chromosomes in the mouse have addressed pathology or phenotype, this study suggests that chromosomal structure can dramatically impact clinical phenotype.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 02 Nov 2025.
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