Human Molecular Genetics Advance Access originally published online on May 20, 2008
Human Molecular Genetics 2008 17(16):2541-2551; doi:10.1093/hmg/ddn154
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Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism
1 INSERM U675, IFR2, Faculté de Médecine Xavier Bichat, Université Denis Diderot-Paris 7, 16 rue Henri Huchard, 75018 Paris, France 2 IntegraGen SA. Genopole, Evry, France 3 UPMC Univ Paris 06, UMRS_592, F-75005, Paris, France 4 INSERM, UMRS_592, Institut de la Vision, F-75012 Paris, France
* To whom correspondence should be addressed. Email: michel.simonneau{at}inserm.fr
Received April 22, 2008; Accepted May 14, 2008
Autism spectrum disorders (ASDs) are common, heritable, but genetically heterogeneous neurodevelopmental conditions. We recently defined a susceptibility locus for ASDs on chromosome 1q41–q42. High-resolution single-nucleotide polymorphisms (126 SNPs) genotyping across the chromosome 1q41–q42 region, followed by a MARK1 (microtubule affinity-regulating kinase 1)-tagged-SNP association study in 276 families with autism from the Autism Genetic Research Exchange, showed that several SNPs within the MARK1 gene were significantly associated with ASDs by transmission disequilibrium tests. Haplotype rs12740310*C-rs3737296*G-rs12410279*A was overtransmitted (Pcorrected= 0.0016), with a relative risk for autism of 1.8 in homozygous carriers. Furthermore, ASD-associated SNP rs12410279 modulates the level of transcription of MARK1. We found that MARK1 was overexpressed in the prefrontal cortex (BA46) but not in cerebellar granule cells, on postmortem brain tissues from patients. MARK1 displayed an accelerated evolution along the lineage leading to humans, suggesting 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 resulted in significantly shorter dendrite length in mouse neocortical neurons and modified dendritic transport speed. As expected for a gene encoding a key polarity determinant Par-1 protein kinase, MARK1 is involved in axon–dendrite specification. Thus, MARK1 overexpression in humans may be responsible for subtle changes in dendritic functioning.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.