De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders
| Autor: | Victor Krajka, Arndt Rolfs, Joanne Trinh, Rami Abou Jamra, Kristian Tveten, Geir J. Braathen, Rabea Affan, Mohammed Al Balwi, Frauke Hinrichs, Øystein L. Holla, Marija Dulovic-Mahlow, Maximilian E. R. Weiss, Nataliya Di Donato, Shivendra Kishore, Skadi Beblo, Martin Werber, Krishna Kumar Kandaswamy, Elisa Rahikkala, Katja Lohmann, Nouriya Al-Sannaa, Øyvind L. Busk, Gabriela Oprea, Hauke Baumann, Nir Navot, Anne-Karin Kahlert, Melissa Vos |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Heterozygote Mutant Protein Serine-Threonine Kinases Mitochondrion Biology Serine 03 medical and health sciences 0302 clinical medicine Mutation Carrier Report Exome Sequencing Genetics Animals Humans Exome Child Gene Genetics (clinical) Gene knockdown Kinase fungi Phenotype Drosophila melanogaster 030104 developmental biology Neurodevelopmental Disorders Mutation Female 030217 neurology & neurosurgery |
| Zdroj: | The American Journal of Human Genetics. 105:213-220 |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|