{
    "abstract": "Germline mutations in the 4 genes (SDHA, SDHB, SDHC, and SDHD) encoding the Succinate Dehydrogenase (SDH) holoprotein are known to predispose towards the development of tumors including pheochromocytomas/paragangliomas (PPGLs), gastrointestinal stromal tumors (GISTs), clear cell renal cancers (RCC), and possibly others. Mutations in these genes have also been described in patients with Cowden Syndrome, which includes tumors of the breast, brain, and thyroid gland. Although nonsense mutations are clearly pathogenic, the functional consequences of many missense mutations are unclear. It has previously been reported that the missense mutations SDHDG12S and SDHDH50R predispose to thyroid and breast cancers, although this characterization has been disputed. To address this question, we developed mouse models to test tumorigenicity of these variants. The reference mouse genome codes for a serine at residue 12 in Sdhd, so this variant was not pursued further. To assess the role of SDHDH50R (H50R), we generated a knock-in mouse allele for this variant and studied its effects in vivo, as well as in vitro in mouse embryonic fibroblasts. Unlike null alleles for Sdhd, the H50R allele did not produce embryonic lethality when homozygous. There was no statistically significant difference in survival or tumor formation in homo- or heterozygous animals compared to littermate controls. In vitro studies similarly failed to detect significant differences in proliferation, colony formation, or metabolic function. Based on our analysis of this allele's function both in vivo and in vitro, we conclude that the SDHDH50R allele is mostly likely a non-pathogenic polymorphism.",
    "authors": [
        {
            "affiliation": "S Priya, Cancer Biology and Genetics, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Shivam",
            "initials": "S",
            "lastname": "Priya"
        },
        {
            "affiliation": "K Chakravarthy, Cancer Biology and Genetics, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Karthik",
            "initials": "K",
            "lastname": "Chakravarthy"
        },
        {
            "affiliation": "E Ziegler, Cancer Biology and Genetics, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Edward",
            "initials": "E",
            "lastname": "Ziegler"
        },
        {
            "affiliation": "X Vesco, Cancer Biology and Genetics, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Xavier",
            "initials": "X",
            "lastname": "Vesco"
        },
        {
            "affiliation": "K LaPerle, Veterinary Biosciences, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Krista",
            "initials": "K",
            "lastname": "LaPerle"
        },
        {
            "affiliation": "X Zhang, Department of Bioinformatics, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Xiaoli",
            "initials": "X",
            "lastname": "Zhang"
        },
        {
            "affiliation": "L Kirschner, Cancer Biology and Genetics, Ohio State University Foundation, Columbus, United States.",
            "firstname": "Lawrence S",
            "initials": "LS",
            "lastname": "Kirschner"
        }
    ],
    "conclusions": null,
    "copyrights": null,
    "doi": "10.1530/ERC-24-0337",
    "journal": "Endocrine-related cancer",
    "keywords": [],
    "methods": null,
    "publication_date": "2025-04-24",
    "pubmed_id": "40272934",
    "results": null,
    "title": "In vivo and in vitro analysis of functional effects of the SDHD H50R variant.",
    "xml": "<Element 'PubmedArticle' at 0x7885033ab010>"
}