2026-04-29T04:08:52Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/189622024-11-29T22:54:14Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Villarroya-Beltri, Carolina author Osorio, Ana author Torres-Ruiz, Raúl author Gómez-Sánchez, David author Trakala, Marianna author Sánchez-Belmonte, Agustin author Mercadillo, Fátima author Hurtado, Begoña author Pitarch, Borja author Hernández-Núñez, Almudena author Gómez-Caturla, Antonio author Rueda, Daniel author Perea, José author Rodriguez Perales, Sandra author Malumbres, Marcos author Urioste, Miguel author 2022-11-04 Germline mutations leading to aneuploidy are rare, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, encoding the spindle assembly checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias. Functional studies demonstrated lack of full-length protein and deficient SAC response, resulting in ~30 to 40% of aneuploid blood cells. Single-cell RNA analysis identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFκB signaling both in aneuploid and euploid cells, suggesting a non-cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of γδ T cells with chromosome 18 gains and enhanced cytotoxic profile as well as intermediate B cells with chromosome 12 gains and transcriptomic signatures characteristic of leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy with systemic inflammation and unprecedented tumor susceptibility. Sci Adv . 2022 ;8(44):eabq591 http://hdl.handle.net/20.500.12105/18962 36322655 10.1126/sciadv.abq5914 2375-2548 Science advances Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility.