De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiency

• DOI: 10.1016/j.isci.2024.109984
• Publication Date: 2024-05-18T06:36:57Z
• Authors: Marina Villamor-Payà; María Sanchiz-Calvo; Jordann Smak; Lynn Pais; Malika Sud; Uma Shankavaram; Alysia Kern Lovgren; Christina Austin-Tse; Vijay S. Ganesh; Marina Gay; Marta Vilaseca; Gianluca Arauz-Ga...; Lluís Palenzuela; Grace VanNoy; Anne O’Donnell-Luria; Travis H. Stracker
• Keywords: REPAIR; CHAPERONE; 0301 basic medicine; Science & Technology; GENES; IDENTIFICATION; MUTATIONS; Science; Q; Article; Multidisciplinary Sciences; neuroscience; immunology; 03 medical and health sciences; DNA-DAMAGE; ASF1; KINASE; Science & Technology - Other Topics; genetics; SPECIFICITY; REQUIRES

The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD) 'Intellectual Disability, Autosomal Dominant 57' (MRD57), characterized by intellectual disability and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a heterozygous TLK1 variant (c.1435C>G, p.Q479E), as well as a mutation in MDM1 (c.1197dupT, p.K400∗). Cells expressing TLK1 p.Q479E exhibited reduced cytokine responses and elevated DNA damage, but not increased radiation sensitivity or DNA repair defects. The TLK1 p.Q479E variant impaired kinase activity but not proximal protein interactions. Our study provides the first functional characterization of NDD-associated TLK1 variants and suggests that, such as TLK2, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.