De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies
| Autor: | Alexander P.A. Stegmann, Tzipora C. Falik-Zaccai, Constance Smith-Hicks, Fernando Kok, Kenneth G. Miller, Constance T. R. M. Stumpel, Konrad Platzer, Maria Teresa Bonati, Laurie A. Demmer, Alexander Pepler, Luiza Ramos, Kaitlin M. Angione, Megan T. Cho, Candace Gamble, Petra Stöbe, Hailey Pinz, Campbell Brasington, Hanna Mandel, Carolyn Wilson, Deepali N. Shinde, Maria Iascone, Rami Abou Jamra, Thorsten Marquardt, Johannes R. Lemke, Heinrich Sticht, Sonal Mahida, Yorck Hellenbroich, Nataliya Di Donato, William Allen, Kirsty McWalter, Stacey L. Edwards, Bianca Panis |
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| Přispěvatelé: | MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine |
| Předmět: |
0301 basic medicine
Male Models Molecular Adolescent PROTEINS EXOME Nerve Tissue Proteins Biology Corpus callosum Article 03 medical and health sciences Young Adult POLYMICROGYRIA 0302 clinical medicine Neurodevelopmental disorder Intellectual Disability Intellectual disability Exome Sequencing Genetics Polymicrogyria medicine Missense mutation Animals Humans Computer Simulation KINESIN Caenorhabditis elegans Child Genetics (clinical) Exome sequencing Adaptor Proteins Signal Transducing AXONAL ANTEROGRADE TRANSPORT MUTATIONS TRKB Brain Perisylvian polymicrogyria medicine.disease Phenotype HEAVY-CHAIN UNC-16 JIP3 030104 developmental biology Child Preschool Mutation Female CRISPR-Cas Systems Lysosomes 030217 neurology & neurosurgery Locomotion |
| Zdroj: | Web of Science American Journal of Human Genetics, 104(2), 203-212. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies. |
| Databáze: | OpenAIRE |
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