A novel genetic strategy to interrogate an unknown phenotypic modifier: an Sdhc KO-Robertsonian mouse with a semi-homologous chromosome develops papillary thyroid carcinoma-like tumours
SDHD and SDHAF2 pathogenic variants confer a remarkable parent-of-origin tumour risk for the neuroendocrine tumours paraganglioma and pheochromocytoma. Paternally transmitted variants cause tumours but maternally transmitted variants do not. The Hensen hypothesis asserts that loss of an (unknown) imprinted gene(s), together 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 paraganglioma model, 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.