PXD019450

PXD019450 is an original dataset announced via ProteomeXchange.

Title	TLK2-associated intellectual disability: report of six novel cases and molecular characterization of p.(Asp551Gly) and p.(Ser617Leu) variants
Description	Introduction The Tousled-Like Kinases 1 and 2 (TLK1 and TLK2) are involved in many fun-damental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently associated with “Mental Retardation Autoso-mal Dominant 57” (MRD57), a neurodevelopmental disorder characterized by a highly varia-ble phenotype, including mild-to-moderate intellectual disability, behavioural abnormalities, facial dysmorphisms, microcephaly, epilepsy and skeletal anomalies. Methods By whole exome sequencing and array-CGH analysis, we identified three independ-ent MRD57 cases. Two were de novo, including a likely pathogenic variant (c.1652A>G; p.(Asp551Gly)) and a 39-kb deletion encompassing TLK2, and one was familial with three sib-lings who inherited a nonsense change from an affected mother (c.1423G>T; p.(Glu475Ter)). Using spatial proteomics (BioID) and single gel electrophoresis, we investigated the proximity interaction landscape of TLK2 and analysed the effects of our missense variant and of another de novo variant reported in the Autism Sequencing Consortium Database (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localization and activity. Results Identified clinical phenotypes were in accordance with previously reported cases. Our molecular results demonstrated that TLK2 activity is strongly impaired by both missense mu-tations and we identified proximal interactions between TLK2 and other factors implicated in neurological disorders, including CHD7, CHD8, BRD4, NACC1 and others. Moreover, we demonstrated a more relaxed state of chromatin in lymphoblastoid cells harbouring the p.(Asp551Gly) variant compared to control cells, which confers susceptibility to DNA damage. Conclusion Our study identified novel TLK2-patients carrying pathogenic variants and pro-vides new insights into their potential role in intellectual disability.
HostingRepository	PRIDE
AnnounceDate	2021-05-13
AnnouncementXML	Submission_2021-05-13_03:09:46.742.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marina Gay
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-05-28 05:08:43	ID requested
⏵ 1	2021-05-13 03:09:47	announced

Pavinato L, Villamor-Pay, à M, Sanchiz-Calvo M, Andreoli C, Gay M, Vilaseca M, Arauz-Garofalo G, Ciolfi A, Bruselles A, Pippucci T, Prota V, Carli D, Giorgio E, Radio FC, Antona V, Giuffr, è M, Ranguin K, Colson C, De Rubeis S, Dimartino P, Buxbaum JD, Ferrero GB, Tartaglia M, Martinelli S, Stracker TH, Brusco A, variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis. J Med Genet, 59(2):170-179(2022) [pubmed]

submitter keyword: intellectual disability, TLK2, comet assay, chromatin condensation, BioID, proximal interac-tome, autism spectrum disorder, tousled like kinases, MRD57

Travis H. Stracker
contact affiliation	Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
contact email	travis.stracker@irbbarcelona.org
lab head
Marina Gay
contact affiliation	Institute for Research in Biomedicine
contact email	marina.gay@irbbarcelona.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD019450
     1. Label: PRIDE project
     2. Name: TLK2-associated intellectual disability: report of six novel cases and molecular characterization of p.(Asp551Gly) and p.(Ser617Leu) variants