EBioMedicine (Jun 2025)

SLK is mutated in individuals with a neurodevelopmental disorderResearch in context

  • Lama Alabdi,
  • Norah Altuwaijri,
  • Jun-yi Zhu,
  • Stephanie Efthymiou,
  • Hangnoh Lee,
  • Jianli Duan,
  • Israa Salem,
  • Piao Yu,
  • Nor Linda Abdullah,
  • Fatema Alzahrani,
  • Qing Xu,
  • Mashael M. Felemban,
  • Abdullah Alfaifi,
  • Fatima Rahman,
  • Marilena Christoforou,
  • Shazia Maqbool,
  • Julian A. Martinez-Agosto,
  • Hessa S. Alsaif,
  • Mais Hashem,
  • Rana Helaby,
  • Ahood Alsulaiman,
  • Reza Maroofian,
  • Henry Houlden,
  • Stefan T. Arold,
  • Leena A. Ibrahim,
  • Zhe Han,
  • Fowzan S. Alkuraya,
  • Stanislav Groppa,
  • Blagovesta Marinova Karashova,
  • Wolfgang Nachbauer,
  • Sylvia Boesch,
  • Larissa Arning,
  • Dagmar Timmann,
  • Bru Cormand,
  • Belen Pérez-Dueñas,
  • Gabriella Di Rosa,
  • Jatinder S. Goraya,
  • Tipu Sultan,
  • Jun Mine,
  • Daniela Avdjieva,
  • Hadil Kathom,
  • Radka Tincheva,
  • Selina Banu,
  • Mercedes Pineda-Marfa,
  • Pierangelo Veggiotti,
  • Michel D. Ferrari,
  • Alberto Verrotti,
  • Giangluigi Marseglia,
  • Salvatore Savasta,
  • Mayte García-Silva,
  • Alfons Macaya Ruiz,
  • Barbara Garavaglia,
  • Eugenia Borgione,
  • Simona Portaro,
  • Benigno Monteagudo Sanchez,
  • Richard Boles,
  • Savvas Papacostas,
  • Michail Vikelis,
  • Eleni Zamba Papanicolaou,
  • Efthymios Dardiotis,
  • Shahnaz Ibrahim,
  • Salman Kirmani,
  • Nuzhat Noureen Rana,
  • Osama Atawneh,
  • George Koutsis,
  • Marianthi Breza,
  • Salvatore Mangano,
  • Carmela Scuderi,
  • Eugenia Borgione,
  • Giovanna Morello,
  • Tanya Stojkovic,
  • Massimo Zollo,
  • Gali Heimer,
  • Yves A. Dauvilliers,
  • Pasquale Striano,
  • Issam Al-Khawaja,
  • Fuad Al-Mutairi,
  • Sherifa Ahmed Hamed,
  • Mohamed A. Abd El Hamed,
  • Samson Khachatryan,
  • Ulviyya Guliyeva,
  • Sughra Guliyeva,
  • Kamran Salayev,
  • Georgia Xiromerisiou,
  • Liana Fidani,
  • Cleanthe Spanaki,
  • Mhammed Aguennouz,
  • Gabriella Silvestri,
  • Chingiz Shashkin,
  • Nazira Zharkynbekova,
  • Kairgali Koneyev,
  • Abdullah Al-Ajmi,
  • Shen-Yang Lim,
  • Farooq Shaikh,
  • Mohamed El Khorassani,
  • Arn M.J.M. van den Maagdenberg,
  • Njideka U. Okubadejo,
  • Oluwadamilola O. Ojo,
  • Kolawole Wahab,
  • Abiodun H. Bello,
  • Sanni Abubakar,
  • Yahaya Obiabo,
  • Ernest Nwazor,
  • Oluchi Ekenze,
  • Uduak Williams,
  • Alagoma Iyagba,
  • Lolade Taiwo,
  • Morenikeji Komolafe,
  • Olapeju Oguntunde,
  • Konstantin Senkevich,
  • Ganieva Manizha,
  • Maksud Isrofilov,
  • Erin Torti,
  • Maha Zaki,
  • Hoda Tomoum,
  • Amira Nabil,
  • Paola Nicolaides,
  • Shahzad Haider,
  • Dana Hasbini,
  • Chadi el Alam,
  • Mona Huneineh,
  • Faisal Zafar,
  • Erum Afzal,
  • Ilyas Muhammad,
  • Atchayaram Nalini,
  • Sofia Bakhtaze,
  • Shahid Baig,
  • Ben Issa,
  • Chahnez Triki,
  • Mussa Bassam,
  • Dana Craiou,
  • Meriem Tazir,
  • Lamia Ali Patcha,
  • Nebal Waill Saadi,
  • Hanene Benrhouma,
  • Payam Saraf,
  • Khalid Hama Salih,
  • Awatif

DOI
https://doi.org/10.1016/j.ebiom.2025.105725
Journal volume & issue
Vol. 116
p. 105725

Abstract

Read online

Summary: 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.

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