2. Academic Validation
  3. De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders

  • Am J Hum Genet. 2019 Jul 3;105(1):213-220. doi: 10.1016/j.ajhg.2019.05.005.
Marija Dulovic-Mahlow 1,  Joanne Trinh 1,  Krishna Kumar Kandaswamy 2,  Geir Julius Braathen 3,  Nataliya Di Donato 4,  Elisa Rahikkala 5,  Skadi Beblo 6,  Martin Werber 2,  Victor Krajka 1,  Øyvind L Busk 3,  Hauke Baumann 1,  Nouriya Abbas Al-Sannaa 7,  Frauke Hinrichs 1,  Rabea Affan 8,  Nir Navot 8,  Mohammed A Al Balwi 9,  Gabriela Oprea 2,  Øystein L Holla 3,  Maximilian E R Weiss 2,  Rami A Jamra 10,  Anne-Karin Kahlert 4,  Shivendra Kishore 2,  Kristian Tveten 3,  Melissa Vos 1,  Arndt Rolfs 11,  Katja Lohmann 12
Affiliations

Affiliations

  • 1 Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany.
  • 2 Centogene AG, 18055 Rostock, Germany.
  • 3 Department of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
  • 4 Institute of Clinical Genetics, Technical University of Dresden, Dresden, Germany.
  • 5 Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO Research Unit) and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90029 OYS Oulu, Finland; Department of Clinical Genetics, Oulu University Hospital, 90029 OYS Oulu, Finland.
  • 6 Institute of Human Genetics, University Hospital Leipzig, 04103 Leipzig, Germany; Center for Pediatric Research Leipzig, Department of Women and Child Health, Hospital for Children and Adolescents, University Hospitals, 04103 Leipzig, Germany.
  • 7 Department of Pediatric Services, Johns Hopkins Aramco Health Care, 34465 Dharan, Saudi Arabia.
  • 8 Pronto Diagnostics, 6158002 Tel Aviv, Israel.
  • 9 Department of Pathology and Laboratory Medicine, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, 11426 Riyadh, Saudi Arabia.
  • 10 Institute of Human Genetics, University Hospital Leipzig, 04103 Leipzig, Germany.
  • 11 Centogene AG, 18055 Rostock, Germany; University of Rostock, 18147 Rostock, Germany.
  • 12 Institute of Neurogenetics, University of Lübeck, 23538 Lübeck, Germany. Electronic address: katja.lohmann@neuro.uni-luebeck.de.
PMID: 31230721 DOI: 10.1016/j.ajhg.2019.05.005
Abstract

De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.

Keywords

TAO kinase 1; de novo variants; fly model; neurodevelopmental disorders.

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