Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism

Abstract

AbstractMicrotubule affinity regulating kinase 4 (MARK4) is a serine/threonine kinase that plays a key role in tau phosphorylation and regulation of the mTOR pathway. Abnormal tau phosphorylation and dysregulation of the mTOR pathway are implicated in neurodegenerative and neurodevelopmental disorders.Here, we report a novel gain-of-function variant inMARK4in two siblings with childhood-onset neurodevelopmental disability and dysmorphic features.The siblings carry a germline heterozygous missenseMARK4variant c.604T>C; p.Phe202Leu, located in the catalytic domain of the kinase, which they inherited from their unaffected, somatic mosaic mother. Functional studies show that this amino acid substitution has no impact on protein expression but instead increases the ability of MARK4 to phosphorylate tau isoforms found in the fetal and adult brain. TheMARK4variant also increases phosphorylation of ribosomal protein S6, indicating upregulation of the mTORC1 pathway.This is the first study to link a germline monoallelicMARK4variant to a childhood-onset neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic features.