Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation. We also showed that LRRTM1 is expressed during the development of specific forebrain structures, and thus could influence neuronal differentiation and connectivity. This is the first potential genetic influence on human handedness to be identified, and the first putative genetic effect on variability in human brain asymmetry. LRRTM1 is a candidate gene for involvement in several common neurodevelopmental disorders, and may have played a role in human cognitive and behavioral evolution.
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The deduced amino acid protein contains an N-terminal signal sequence, followed by 10 extracellular LRRs flanked by cysteine-rich domains, a transmembrane region, and an intracellular tail. Lauren et al. Orthologs of LRRTM1 were detected in databases derived from several vertebrate species but not in databases derived from Drosophila or C.
RT-PCR analysis of human tissues detected highest LRRTM1 expression in salivary gland and in brain, including hippocampus, thalamus, caudate nucleus, corpus callosum, and amygdala. Expression was intermediate in cerebellum, small intestine, spinal cord, stomach, testis, and uterus.
In developing mice, Lrrtm1 was expressed at embryonic day 13 and Highest levels were reached at postnatal day 1 and persisted into adulthood. In situ hybridization of adult mouse brain detected widespread Lrrtm1 expression predominantly in neurons.
The block in LTP could be rescued by expression of full-length Lrrtm2 or Lrrtm2 lacking its intracellular domain, but not by Lrrtm4 Detailed examination of the rescue effect by Lrrtm2 using a molecular replacement strategy revealed that the extracellular leucine-rich repeat domains of Lrrtm2 and binding to neurexins see are involved in LTP.
Gene deletion of Lrrtm1 and Lrrtm2 in young adult mice reduced the AMPAR-mediated synaptic transmission but had no detectable effect on presynaptic function. Imaging of recombinant photoactivatable AMPAR subunit GluA1 in the dendritic spines of cultured mouse neurons demonstrated that the double deletion of Lrrtm1 and Lrrtm2 reduced the stability of GluA1 and resulted in a faster loss of the GluA1 spine signal.
Bhouri et al. They mapped the mouse Lrrtm1 gene to chromosome 6C3, which shares homology of synteny with human chromosome 2p A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics ,
Leucine-rich repeat transmembrane neuronal protein 1
Mol Psychiatry. Epub Jul LRRTM1 on chromosome 2p12 is a maternally suppressed gene that is associated paternally with handedness and schizophrenia. Left-right asymmetrical brain function underlies much of human cognition, behavior and emotion. Abnormalities of cerebral asymmetry are associated with schizophrenia and other neuropsychiatric disorders. The molecular, developmental and evolutionary origins of human brain asymmetry are unknown. We then found direct confirmatory evidence that LRRTM1 is an imprinted gene in humans that shows a variable pattern of maternal downregulation.