PXD035765

PXD035765 is an original dataset announced via ProteomeXchange.

Title	Bilallelic germline mutations in MAD1L1 induce a novel syndrome of aneuploidy with high tumor susceptibility
Description	Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, the gene encoding the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias, including five malignant tumors. Functional studies in peripheral blood cells demonstrated lack of full-length protein and deficient SAC response, resulting in ~30-40% of aneuploid cells as detected by cytogenetic and single-cell (sc) DNA analysis. scRNA-seq analysis of proband blood cells identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFkB signaling. The inference of chromosomal aberrations from scRNA-seq analysis detected inflammatory signals both in aneuploid and euploid cells, suggesting a non-cell autonomous response to aneuploidy. In addition to random aneuploidies, MAD1L1 mutations resulted in specific clonal expansions of 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 chronic lymphocytic leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy syndrome (MVA) with systemic inflammation and unprecedented tumor susceptibility.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:42:36.274.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eduardo Zarzuela
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-02 10:48:46	ID requested
1	2023-03-11 04:11:05	announced
⏵ 2	2023-11-14 08:42:42	announced	2023-11-14: Updated project metadata.

Villarroya-Beltri C, Osorio A, Torres-Ruiz R, G, ó, mez-S, á, nchez D, Trakala M, S, á, nchez-Belmonte A, Mercadillo F, Hurtado B, Pitarch B, Hern, á, ndez-N, ú, ñ, ez A, G, ó, mez-Caturla A, Rueda D, Perea J, Rodr, í, guez-Perales S, Malumbres M, Urioste M, Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility. Sci Adv, 8(44):eabq5914(2022) [pubmed]

submitter keyword: Human, MVA,MAD1L1

Eduardo Zarzuela
contact affiliation	CNIO
contact email	ezarzuela@cnio.es
lab head
Eduardo Zarzuela
contact affiliation	Centro Nacional de Investigaciones Oncológicas
contact email	eduzarfer@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035765
     1. Label: PRIDE project
     2. Name: Bilallelic germline mutations in MAD1L1 induce a novel syndrome of aneuploidy with high tumor susceptibility