A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases for the SPARK cohort, in Zhou et al., 2022 identified MARK2 as a gene reaching exome-wide significance (P < 2.5E-06); association of MARK2 with ASD risk was primarily driven by de novo variants. A de novo missense variant in MARK2 was also identified in an ASD proband from the SAGE cohort in Guo et al., 2019. More recently, Gong et al., 2024 reported 31 individuals with MARK2 variants presenting with autism spectrum disorder (30/31, 96.8%), developmental delay/intellectual disability (29/29, 100%), speech/language problems (31/31, 100%), additional behavioral abnormalities (20/27, 74.1%), and distinctive recurrent facial features including a narrow face, abnormal or broad forehead, downslanting palpebral fissures, and large or dysplastic ears. Moreover, Gong et al., 2024 demonstrated that MARK2 loss in either proband-derived or CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs) led to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs), while Mark2+/- mice showed abnormal cortical formation and partition and ASD-like behavior.
Molecular Function
This gene encodes a member of the Par-1 family of serine/threonine protein kinases. The protein is an important regulator of cell polarity in epithelial and neuronal cells, and also controls the stability of microtubules through phosphorylation and inactivation of several microtubule-associating proteins. The protein localizes to cell membranes.
The Mark2 knockout mouse shows abnormal spine morphology, with an increase in immature spines. The knockout shows a decrease in mEPSC frequency and behavioral deficits in spatial memory, active avoidance, social approach and anxiety. The heterozygote haploinsufficiency model shows milder phenotypes, including an imbalance of neuronal proliferation and differentiation, resulting in abnormal cortical lamination. The heterozygote also shows ASD-like phenotypes like decreased social approach and social memory and increased repetitive digging and self-grooming behavior.
References
Type
Title
Author, Year
Additional
MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Knockout allele was generated using CRISPR-Cas-mediated genome engineering to delete exons 2-17 of Mark2.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: Not specified
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Cyagen Biosciences (China)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Knockout allele (MGI:2182819) replaces exons 2, 3 and 4 with a neomycin cassette. The deleted region encodes a glycine-rich motif involved in MgATP-binding.
Allele Type: Knockout
Strain of Origin: 129X1/SvJ
Genetic Background: C57BL/6J
ES Cell Line: RW-4
Mutant ES Cell Line: Model Source: Jackson Laboratory
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Knockout allele (MGI:2182819) replaces exons 2, 3 and 4 with a neomycin cassette. The deleted region encodes a glycine-rich motif involved in MgATP-binding.
Allele Type: Knockout
Strain of Origin: 129X1/SvJ
Genetic Background: C57BL/6J
ES Cell Line: RW-4
Mutant ES Cell Line: Model Source: Jackson Laboratory
Description: Knockout mice show an increased number of thin spines and reduced number of mushroom spines, but no overall differences across genotypes for length, width.
Exp Paradigm: YFP
Description: Heterozygous mice show an increased number of thin spines and reduced number of mushroom spines, but no overall differences across genotypes for length, width.
Exp Paradigm: YFP
