De novo variants in the MAP1B gene, including three loss-of-function variants, have been reported in individuals with a clinical diagnosis of ASD (De Rubeis et al., 2014; Satterstrom et al., 2020; Zhou et al., 2022; Spataro et al., 2023). Heterozygous mutations in MAP1B are also responsible for periventricular nodular heterotopia-9 (OMIM 618918), an autosomal dominant neurologic disorder characterized by malformation of cortical development (including anterior predominant PVNH, thin corpus callosum, and decreased white matter volume), developmental delay, cognitive defects associated with low IQ (range 50 to 80), learning disabilities, seizures, and behavior abnormalities; autism spectrum disorder was reported in a subset of affected individuals with this disorder (Heinzen et al., 2018; Walters et al., 2018; Julca et al., 2019; Arya et al., 2021). MAP1B has been shown to interact with FMRP, the protein encoded by the FMR1 gene, as well as with the protein encoded by the KIRREL3 gene (Zhang et al., 2001; Liu et al., 2015).
Molecular Function
This gene encodes a protein that belongs to the microtubule-associated protein family. The proteins of this family are thought to be involved in microtubule assembly, which is an essential step in neurogenesis. The product of this gene is a precursor polypeptide that presumably undergoes proteolytic processing to generate the final MAP1B heavy chain and LC1 light chain. Gene knockout studies of the mouse microtubule-associated protein 1B gene suggested an important role in development and function of the nervous system.
To model MAP1B triplication in ASD proband, an overexpression mouse model was developed, in which the Map1b gene is specifically overexpressed in excitatory neurons of the prefrontal cortex. The mouse model shows social approach and social memory deficits in the three-chamer sociability test. This overexpression model, however, shows no changes in locomotor activity, repetitive behavior, anxiety or spatial memory.
Model Type:
Genetic
Model Genotype:
Transgene
Mutation:
Cloned Map1b sgRNA in an adeno associate viral (AAV) vector was used to generate recombinant AAV-sgMap1b (AAV8-sgMap1b-hSyn1- flex-mCherry) virus. The AAV-sgMap1b virus (or control AAV-sgCtrl) was stereotaxically injected together with AAV-pCamk2a-GFP-Cre that expresses Cre recombinase in Camk2a-expressing excitatory neurons, into the medial prefrontal cortex of Cre-dependent dCas9-Activator mice (MGI:6149220). Mice with targeted activation of the endogenous Map1b gene (AAV-sgMap1b injected) have 2.2-fold higher MAP1B protein levels in excitatory neurons in the prefrontal cortex, compared to controls (AAV-sgCtrl injected).
Allele Type: Overexpression
Strain of Origin: (C57BL/6 x DBA/2J)F1
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source:
