Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis

Medientyp: E-Artikel
Titel: Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis
Beteiligte: Pavinato, Lisa; Villamor-Payà, Marina; Sanchiz-Calvo, Maria; Andreoli, Cristina; Gay, Marina; Vilaseca, Marta; Arauz-Garofalo, Gianluca; Ciolfi, Andrea; Bruselles, Alessandro; Pippucci, Tommaso; Prota, Valentina; Carli, Diana; Giorgio, Elisa; Radio, Francesca Clementina; Antona, Vincenzo; Giuffrè, Mario; Ranguin, Kara; Colson, Cindy; De Rubeis, Silvia; Dimartino, Paola; Buxbaum, Joseph D; Ferrero, Giovanni Battista; Tartaglia, Marco; Martinelli, Simone; [...]
Erschienen: BMJ, 2022
Erschienen in: Journal of Medical Genetics
Sprache: Englisch
DOI: 10.1136/jmedgenet-2020-107281
ISSN: 0022-2593; 1468-6244
Schlagwörter: Genetics (clinical) ; Genetics
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Beschreibung: <jats:sec><jats:title>Introduction</jats:title><jats:p>The Tousled-like kinases 1 and 2 (TLK1 and TLK2) are involved in many fundamental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in <jats:italic>TLK2</jats:italic> were recently associated with ‘Mental Retardation Autosomal Dominant 57’ (MRD57, MIM# 618050), a neurodevelopmental disorder characterised by a highly variable phenotype, including mild-to-moderate intellectual disability, behavioural abnormalities, facial dysmorphisms, microcephaly, epilepsy and skeletal anomalies.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We re-evaluate whole exome sequencing and array-CGH data from a large cohort of patients affected by neurodevelopmental disorders. Using spatial proteomics (BioID) and single-cell gel electrophoresis, we investigated the proximity interaction landscape of <jats:italic>TLK2</jats:italic> and analysed the effects of p.(Asp551Gly) and a previously reported missense variant (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localisation and activity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified three new unrelated MRD57 families. Two were sporadic and caused by a missense change (c.1652A>G; p.(Asp551Gly)) or a 39 kb deletion encompassing <jats:italic>TLK2</jats:italic>, and one was familial with three affected siblings who inherited a nonsense change from an affected mother (c.1423G>T; p.(Glu475Ter)). The clinical phenotypes were consistent with those of previously reported cases. The tested mutations strongly impaired <jats:italic>TLK2</jats:italic> kinase activity. Proximal interactions between TLK2 and other factors implicated in neurological disorders, including CHD7, CHD8, BRD4 and NACC1, were identified. Finally, we demonstrated a more relaxed chromatin state in lymphoblastoid cells harbouring the p.(Asp551Gly) variant compared with control cells, conferring susceptibility to DNA damage.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our study identified novel <jats:italic>TLK2</jats:italic> pathogenic variants, confirming and further expanding the MRD57-related phenotype. The molecular characterisation of missense variants increases our knowledge about TLK2 function and provides new insights into its role in neurodevelopmental disorders.</jats:p></jats:sec>

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