SLK is mutated in individuals with a neurodevelopmental disorder.

BACKGROUND: Key to neuronal cell polarization and maturation is proper cytoskeletal organization and function that endows the bipolar neuronal cell with mature dendrites, axons, and functional synapses. Ste20-like kinase (SLK) has been shown to have various cytoskeletal roles. SLK regulates the polarity of microtubules, and its deficiency in the developing murine cortex leads to major defects including impaired development of the distal dendritic tree. No neurodevelopmental phenotypes in humans, however, have been linked to SLK. METHODS: Clinical phenotyping, positional mapping, exome sequencing and functional analyses using patient-derived cells, SLK knock down cell lines, as well as a Drosophila model of Slik deficiency (the orthologue of SLK). FINDINGS: We identified three individuals from three families (two are consanguineous) in whom a neurodevelopmental disorder (NDD) is linked to biallelic variants in SLK. The deleterious nature of these variants is confirmed by their failure to rescue the abnormal synapse maturation and locomotor defects phenotype in a Drosophila model of Slik deficiency. We also recapitulated the previously published abnormal cytoskeletal phenotype using patient cells, which showed abnormal organization of the cytoskeleton with accompanying impairment of migration and polarization. Furthermore, transdifferentiated neurons from patient fibroblasts displayed immature neuronal-like morphology with reduced dendritic arborization. INTERPRETATION: Our results support an autosomal recessive SLK-related NDD and suggest abnormal cytoskeleton-mediated neuronal maturation as the underlying mechanism. FUNDING: MRC (MR/S01165X/1, MR/S005021/1, G0601943, MR/S005021/1), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). National Institutes of Health (NIH) grants HL134940 and DK098410. King Abdullah University of Science and Technology (KAUST) through the baseline fund to STA and LI as well as to STA and LI, and the KAUST Center of Excellence for Smart Health (KCSH), under award number 5932.