De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies

Journal article

Publication Details

Author(s): Platzer K, Sticht H, Edwards SL, Allen W, Angione KM, Bonati MT, Brasington C, Cho MT, Demmer LA, Falik-Zaccai T, Gamble CN, Hellenbroich Y, Iascone M, Kok F, Mahida S, Mandel H, Marquardt T, Mcwalter K, Panis B, Pepler A, Pinz H, Ramos L, Shinde DN, Smith-Hicks C, Stegmann APA, Stoebe P, Stumpel CTRM, Wilson C, Lemke JR, Di Donato N, Miller KG, Jamra R
Journal: American Journal of Human Genetics
Publication year: 2019
Volume: 104
Journal issue: 2
Pages range: 203-212
ISSN: 0002-9297


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.

FAU Authors / FAU Editors

Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik

External institutions with authors

Ambry Genetics
Azienda Ospedaliera Papa Giovanni XXIII
CeGaT GmbH
Galilee Medical Center / המרכז הרפואי לגליל
Istituto Scientifico Ospedale San Luca (Istituto Auxologico Italiano)
Johns Hopkins University
Levine Children’s Hospital
Maastricht University
North Carolina Biotechnology Center
Oklahoma Medical Research Foundation (OMRF)
Saint Louis University (SLU)
Technische Universität Dresden
Universitätsklinikum Leipzig
Universitätsklinikum Münster
Universität zu Lübeck
University of Colorado System
University of Texas Health Science Center at Houston (UTHealth)

How to cite

Platzer, K., Sticht, H., Edwards, S.L., Allen, W., Angione, K.M., Bonati, M.T.,... Jamra, R. (2019). De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies. American Journal of Human Genetics, 104(2), 203-212.

Platzer, Konrad, et al. "De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies." American Journal of Human Genetics 104.2 (2019): 203-212.


Last updated on 2019-12-03 at 08:53