Relevance to Autism

Multiple de novo variants in the MACF1 gene, including several missense variants, have been identified in ASD probands (Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020; Zhou et al., 2022), while inherited missense variants in this gene were identified in at least two diagnosed autistic individuals and absent in all non-autistic individuals in two separate multiplex ASD families in More et al., 2023. Heterozygous mutations in MACF1 are responsible for lissencephaly-9 with complex brainstem malformation (LIS9; OMIM 618325), an autosomal dominant neurologic disorder characterized by global developmental delay apparent since infancy, impaired intellectual development with poor or absent speech, and sometimes abnormal or involuntary movements associated with abnormal brain imaging that typically shows pachygyria, lissencephaly, and malformation of the brainstem consistent with a neuronal migration defect (Dobyns et al., 2018); two of the eight individuals with this disorder in this report presented with hand stereotypies. Macf1-mutant mice have been shown to exhibit social deficits and aberrant emotional behaviors (Ka et al., 2022).

Molecular Function

This gene encodes a large protein containing numerous spectrin and leucine-rich repeat (LRR) domains. The encoded protein is a member of a family of proteins that form bridges between different cytoskeletal elements. This protein facilitates actin-microtubule interactions at the cell periphery and couples the microtubule network to cellular junctions. Deletion of Macf1 in the mouse cerebral cortex during cortical development results in double cortex/subcortical band heterotopia and disrupted cortical lamination (Ka et al., 2022).

External Links

References