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Autism spectrum disorders (ASDs) are genetically heterogeneous neurodevelopmental conditions. Application of a direct physical identity-by-descent mapping approach to perform a high-density genome-wide linkage allowed the identification of novel loci (Philippi et al, 2005, Molecular Psychiatry).
Objectives: The objective of this work was to identify an associated gene on chromosome 1q41-q42 and to define its functional involvement in ASDs.
Methods: Association studies in 276 ASD families from the Autism Genetic Research Exchange, measurements of MARK1 transgene expression as a function of human regulatory region haplotypes, quantification of transcripts in post-mortem human brain tissues from Autism Tissue Program and in vitro analysis of Mark1 overexpression and down regulation by shRNAs in mouse cortical neurons have been performed.
Results:
High-resolution genotyping of 126 single-nucleotide polymorphisms across the 1q41-q42 region, followed by a MARK1-tagged-SNP association study allowed to identify MARK1 SNPs significantly associated with ASDs by transmission disequilibrium tests. Furthermore, haplotype rs12740310*C-rs3737296*G-rs12410279*A was overtransmitted (Pcorrected=0.0016) with a relative risk for autism of 1.8. The transcription level of MARK1 is modulated by the ASD-associated SNP rs12410279. MARK1 is overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells from patients. Accelerated evolution displayed by MARK1 along the lineage leading to humans suggests a possible involvement of this gene in cognition. MARK1 encodes a kinase-regulating microtubule-dependent transport in axons and dendrites. Both overexpression and silencing of MARK1 showed a significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed. MARK1 is involved in axon-dendrite specification, as expected for a gene encoding a key polarity determinant Par-1 protein kinase.
Conclusions: MARK1 could be responsible for subtle changes in dendritic functioning in ASD patients. We previously reported that SLC25A12 is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects (Lepagnol-Bestel et al, 2008, Molecular Psychiatry). Altogether these results demonstrate that deregulations of genes encoding proteins involved in dendritic trafficking can contribute to ASDs.
Human brain samples were obtained from Autism Tissue Program. This work was partially funded by INSERM, Fondation