Pavinato, Lisa ORCID: 0000-0002-7630-8365, Villamor-Paya, Marina ORCID: 0000-0002-7288-4197, Sanchiz-Calvo, Maria, Andreoli, Cristina ORCID: 0000-0003-3724-0668, Gay, Marina ORCID: 0000-0002-8827-7092, Vilaseca, Marta ORCID: 0000-0002-1666-1300, Arauz-Garofalo, Gianluca ORCID: 0000-0001-5166-6054, Ciolfi, Andrea ORCID: 0000-0002-6191-0978, Bruselles, Alessandro ORCID: 0000-0002-1556-4998, Pippucci, Tommaso, Prota, Valentina ORCID: 0000-0003-2336-9954, Carli, Diana ORCID: 0000-0001-5690-6504, Giorgio, Elisa ORCID: 0000-0003-4076-4649, Radio, Francesca Clementina, Antona, Vincenzo, Giuffre, Mario, Ranguin, Kara, Colson, Cindy, De Rubeis, Silvia, Dimartino, Paola ORCID: 0000-0002-6521-1082, Buxbaum, Joseph D., Ferrero, Giovanni Battista, Tartaglia, Marco ORCID: 0000-0001-7736-9672, Martinelli, Simone, Stracker, Travis H. and Brusco, Alfredo ORCID: 0000-0002-8318-7231 (2022). Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis. J. Med. Genet., 59 (2). S. 170 - 180. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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Abstract

Introduction 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 TLK2 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. Methods 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 TLK2 and analysed the effects of p.(Asp551Gly) and a previously reported missense variant (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localisation and activity. Results 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 TLK2, 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 TLK2 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. Conclusion Our study identified novel TLK2 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pavinato, LisaUNSPECIFIEDorcid.org/0000-0002-7630-8365UNSPECIFIED
Villamor-Paya, MarinaUNSPECIFIEDorcid.org/0000-0002-7288-4197UNSPECIFIED
Sanchiz-Calvo, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andreoli, CristinaUNSPECIFIEDorcid.org/0000-0003-3724-0668UNSPECIFIED
Gay, MarinaUNSPECIFIEDorcid.org/0000-0002-8827-7092UNSPECIFIED
Vilaseca, MartaUNSPECIFIEDorcid.org/0000-0002-1666-1300UNSPECIFIED
Arauz-Garofalo, GianlucaUNSPECIFIEDorcid.org/0000-0001-5166-6054UNSPECIFIED
Ciolfi, AndreaUNSPECIFIEDorcid.org/0000-0002-6191-0978UNSPECIFIED
Bruselles, AlessandroUNSPECIFIEDorcid.org/0000-0002-1556-4998UNSPECIFIED
Pippucci, TommasoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prota, ValentinaUNSPECIFIEDorcid.org/0000-0003-2336-9954UNSPECIFIED
Carli, DianaUNSPECIFIEDorcid.org/0000-0001-5690-6504UNSPECIFIED
Giorgio, ElisaUNSPECIFIEDorcid.org/0000-0003-4076-4649UNSPECIFIED
Radio, Francesca ClementinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antona, VincenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giuffre, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ranguin, KaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colson, CindyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Rubeis, SilviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dimartino, PaolaUNSPECIFIEDorcid.org/0000-0002-6521-1082UNSPECIFIED
Buxbaum, Joseph D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferrero, Giovanni BattistaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tartaglia, MarcoUNSPECIFIEDorcid.org/0000-0001-7736-9672UNSPECIFIED
Martinelli, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stracker, Travis H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brusco, AlfredoUNSPECIFIEDorcid.org/0000-0002-8318-7231UNSPECIFIED
URN: urn:nbn:de:hbz:38-693665
DOI: 10.1136/jmedgenet-2020-107281
Journal or Publication Title: J. Med. Genet.
Volume: 59
Number: 2
Page Range: S. 170 - 180
Date: 2022
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SPECTRUM; MUTATIONS; PHENOTYPE; PROTEINS; GENOTYPE; GENES; RISK; CHD7; RNAMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69366

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