Journal article
Loss-of-Function Variants in MARK2 Cause Neurodevelopmental Disorder
HGG advances, 100600
03/30/2026
DOI: 10.1016/j.xhgg.2026.100600
PMID: 41918168
Abstract
Microtubule-affinity regulating kinase 2 (MARK2) is a conserved serine/threonine kinase that plays a critical role in microtubule dynamics and neuronal polarity. Rare MARK2 variants have recently been reported in individuals with autism spectrum disorder (ASD) and neurodevelopmental delay (NDD) [1-3], and here we expand the number of affected individuals, including a familial case. Despite these clinical findings, the functional significance and underlying mechanisms of patient-derived variants remain poorly understood. To address this gap, we established a humanized Drosophila model and systematically evaluated eight NDD-linked MARK2 variants using tissue-specific expression assays. Functional assessments in Drosophila indicate that MARK2 variants span a range of functional consequences, primarily exhibiting hypomorphic or loss-of-function effects. Truncating variants consistently showed reduced protein levels and rescued lethality, a loss-of-function mechanism. Most missense variants (e.g., p.Val231Met, p.Gly135Arg, p.Ala80Val, p.His167Pro) maintained protein expression and induced mild to moderate phenotypes, consistent with partial loss-of-function. The p.Lys224Glu variant behaved similarly to wild-type in both viability and wing patterning assays and exhibited elevated protein levels, but did not display overt pathogenicity in flies. Based on these findings, we propose a functional classification of MARK2 variants into three categories: not pathogenic (p.Lys224Glu), hypomorphic (missense variants), and loss-of-function (truncating variants). These results highlight the value of Drosophila as a scalable in vivo platform for variant interpretation and provide insight into how reduced MARK2 activity may contribute to neurodevelopmental disorders.
Details
- Title: Subtitle
- Loss-of-Function Variants in MARK2 Cause Neurodevelopmental Disorder
- Creators
- Yunseon Yang - Houston MethodistYoon-Kyung Shim - Houston MethodistNoriko Miyake - National Center for Global Health and MedicineSanami Takada - National Center for Global Health and MedicineSebastian Silva - San Sebastián UniversityAlexander Peters-Foitzick - San Sebastián UniversityAbha R Gupta - Yale UniversityEmily Neuhaus - Behavioral Tech Research, Inc.Catherine Bradley - Medical University of South CarolinaCora Taylor - Autism & Developmental Medicine InstituteBianca Russell - University of California, Los AngelesAmanda Shrewsbury - University of California, Los AngelesJacob J Michaelson - University of IowaChaya N Murali - Texas Children's HospitalAmanda Gerard - Texas Children's HospitalAlexa Geltzeiler - Boston Children's HospitalWendy K Chung - Boston Children's HospitalHyung-Lok Chung - Houston Methodist
- Resource Type
- Journal article
- Publication Details
- HGG advances, 100600
- DOI
- 10.1016/j.xhgg.2026.100600
- PMID
- 41918168
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- Elsevier Inc.
- Language
- English
- Electronic publication date
- 03/30/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Communication Sciences and Disorders; Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9985149705302771
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