LRRTM1 leucine rich repeat transmembrane neuronal 1 [ (human)]. Gene ID: , updated on 7-Dec This gene is imprinted, being predominantly expressed from the paternal allele and showing a variable pattern of maternal down-regulation. May be associated . Leucine-rich repeat transmembrane neuronal protein 1. Gene. Lrrtm1. Organism. Mus musculus (Mouse). Status. Reviewed-Annotation score: Annotation.
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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 lrrt,1 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.
Left—right asymmetrical function is a conserved feature of vertebrate central nervous systems. This association is likely to be partly genetic in etiology.
We performed previously the first genome-wide linkage scan for a quantitative measure of human handedness 5 relative hand skill; assessed with timed peg moving 5and found linkage on 2p12—q Schizophrenia is associated with reductions or reversals of normal cerebral asymmetries, including the medial temporal lobe, superior temporal gyrus, planum temporale and the overall brain anterior—posterior torque. However, this gene has not so far been shown to be linked to asymmetry, language or psychosis.
In a recent meta-analysis of 20 linkage screens for schizophrenia, 2p12—q22 was the only location to reach significance when adjusted for genome-wide testing. In the present study we have used genetic association mapping and gene-functional analysis to identify a novel imprinted gene on 2p12, LRRTM1, that we propose is responsible for causing the linkages of this chromosomal region to human handedness and schizophrenia.
All work involving human samples and materials was approved by the appropriate institutional review boards, and appropriate informed consent was obtained from all human subjects. Details of the Materials and methods are given in Supplementary information online. We genotyped 87 single-nucleotide polymorphisms SNPs in RD siblings and their parents, within a region of paternal-specific linkage to relative hand skill that we had detected previously in this sample Figure 1.
Following our parent-of-origin linkage data Figure 1we tested for quantitative association of paternally inherited SNP alleles with relative hand skill using QTDT Four SNPs in distinct locations rs, rs, rs and rs; Table S1which were not in significant linkage disequilibrium LD with one another, showed nominally significant paternal-specific association with relative hand skill 0.
This was no more than the expected false-positive rate.
RCSB PDB – Gene View – LRRTM1 – leucine rich repeat transmembrane neuronal 1
Mapping of an imprinted quantitative-trait-locus QTL for human handedness. Significance of linkage is shown on a logarithmic scale. The final SNP map that we used in this region is shown see also Table S1and the three SNPs that showed the initial paternal-specific haplotype associations are highlighted by pink circles rsrsrs We used the total, paternal and multi-allelic options of QTDT together for the association tests.
The rsrsrs haplotype where 2 is the minor allele of each SNP was responsible primarily for the paternal-specific association observed with haplotypes derived from these three SNPs.
We screened the first two exons and predicted promoter of LRRTM1 for polymorphisms in 26 left-handers from the RD sample by denaturing high-performance liquid chromatography and sequencing, but we did not detect any polymorphisms that tagged rsrsrs haplotypeor that had overt disruptive effects on the predicted LRRTM1 protein entirely coded within exon 2. We genotyped the SNPs rs and either rs or rs the latter are equivalent tagging SNPs according to international HapMap data in four family samples of white European descent that included individuals with schizophrenia or poor-outcome schizoaffective disorder.
The haplotype defined by the rare alleles of these SNPs is equivalent to the risk haplotype for left-handedness defined above Figure S1. The haplotype varied in frequency between 7. This was a specific hypothesis test that requires no statistical adjustment.
There was no significant paternal overtransmission of any other haplotype, nor was there maternal overtransmission of any haplotype. The paternal result was derived roughly equally from three of the four samples Table 1. We genotyped rs almost tagging for the risk haplotype; Figure S1in two case—control collections of European descent cases and controls from Munich, Germany, and cases and controls from Scotland all cases had Diagnostic and Statistical Manual of Mental Disordersfourth edition diagnoses of schizophrenia, and both sample sets were recruited according to the same protocol.
We also tested for association in a sample of Han Chinese families 23 but we found no significant bias in paternal or maternal transmission of any haplotype to schizophrenic people there were 65 paternal transmissions to 78 paternal nontransmissions of the haplotype.
No imprinted genes were known previously on chromosome 2p. We found that human LRRTM1 is imprinted paternal-only expression in hybrid A9 cells 24 mouse cell lines containing single human chromosomes of known parental origin Figure 2. Despite certain limitations with hybrid cells in the context of imprinting genee, 25 mouse A9 cells have been used for the reliable identification and verification of human imprinted genes.
We detected the expression of all four genes in chromosome 2 hybrid cells, regardless of the parental origin gee the human chromosome 2 Figure S2. No detection of these genes was obtained in RT- controls. We also used transcribed polymorphisms to show mono-allelic LRRTM1 expression in tissue samples from a minority of unrelated postmortem human brains 3 out of 18 by RT-PCR and sequencing or restriction digestion not shown.
However, biallelic expression was found in 15 out of 18 brains, and LRRTM1 was expressed at similar levels from both alleles in the adult human gnee cortex of five individuals showing biallelic expression analyzed by quantitative PCR. All brain tissue was obtained from normal controls that were unaffected by major neurological or psychiatric disease. LRRTM1 expression is downregulated maternally in humans.
C2 is a human fibroblast cell line. By use of in situ hybridization in the mouse, we found that Lrrtm1 is expressed predominantly in lfrtm1 nervous system by lrrtn1 neurons, but also in some nonneuronal tissues Figure 3 ; Figure S3. Expression is upregulated in the mouse brain during embryonic development and early postnatally. In adult brain, Lrrtm1 expression is most prominent in the forebrain, particularly in the thalamus in most or all nucleiand in cortical areas including hippocampus, genne and posterior cingulate Figure 3 ; Figure S3.
In situ lrrt1m analysis in sagittal sections of E15 mouse embryos a and b and coronal sections of adult mouse brain c—f. Bright-field images counterstained with hematoxylin a, c and e and corresponding dark-field autoradiographs are shown b, d and f. The white signal in the dark-field images indicates Lrrtm1 expression.
LRRTM1 – Wikipedia
LRRTM1 is localized to the cell soma and in the neurites; in neurites it is also localized to lamellipodia of the growth cones arrowheads in h and i.
In northern blot analysis of adult human brain, LRRTM1 also showed predominant expression in forebrain regions including thalamus and cerebral cortex Figure S4. By in situ hybridization in coronal sections of the post-mortem developing human brain 14—16 weeks gestation; Figure 4strong expression was observed in anterior sections throughout the cortical plate and in septum, caudate and putamen.
The absence of signal in the subventricular zone argues against a direct involvement in neurogenesis Figure 4. Transcript distribution was similar in more caudal sections with the addition of signal in dorsolateral thalamus Figure 4. More caudal still, thalamic signal shifted ventrally to a structure consistent with the lateral geniculate body Figure 4.
The striking signal in caudate and putamen in human Figure 4 was not present in mouse, at least not at E15 and in adult. In addition, expression within the human thalamus was more restricted as compared to the mouse, with staining relatively limited to dorsomedial regions. In coronal sections of anterior brain aexpression is strong throughout the cortical plate and otherwise restricted to septum, caudate, and putamen.
Transcript distribution is similar in more caudal sections b with the addition of signal in dorsolateral thalamus. More caudal still cthalamic signal shifts ventrally to a structure consistent with the lateral geniculate body. Abbreviations are as follows: Similarly to embryonic brain, LRRTM1 was expressed at similar levels that is, symmetrically in all analyzed regions of left and right adult human cerebral cortex several different cortical regions from five individuals were analyzed by quantitative PCR.
We also quantified left- and right-brain Lrrtm1 mRNA expression levels in rats and embryonic mice see Materials and methodsbut did not detect evidence for asymmetrical expression in rodents. Each of the F1 mice was 30 weeks old. Expression of Lrrtm1 was detected in cerebral cortex, cerebellum and brain stem, but it was biallelic Figure S5.
Live-cell staining for overexpressed LRRTM1 in DRG neurons revealed that the protein is not accessible on the plasma membrane under conditions that allowed surface detection of a related member of the LRR protein superfamily, Lingo1 Figure 5. These results suggest that endogenous LRRTM1 may have a role in intracellular trafficking within axons.
LRRTM1 is not localized on the plasma membrane. No cell-surface expression of LRRTM1 is seen in primary sensory neurons electroporated with myc-LRRTM1 construct and detected by live-cell staining with alkaline phosphatase-conjugated anti-myc antibody a ; strong cell-surface staining of myc-Lingo1 expressing neuron is seen b. Similarly, in neuro-2a neuroblastoma cells myc-LRRTM1 c is not, but myc-lingo1 is d localized to plasma membrane as detected by live-cell staining.
We analyzed methylation within 2 CpG islands that correspond to the predicted promoter and coding exon of LRRTM1, and a third island roughly 18 kb upstream of LRRTM1, in 17 lymphoblastoid cell lines and 17 human post-mortem brain samples, but we did not find evidence that these CpG islands are differentially methylated regions DMRs data not shown. There are no other genes within 1.
There is no fixed amino acid difference between human LRRTM1 and chimpanzee LRRTM1, and it is not among the genes that are differently expressed between adult humans and adult chimpanzees in brain, liver, kidney, heart or testis. Crow proposed that handedness, brain asymmetry and schizophrenia share an underlying genetic relationship.
We carried hene SNP-based association screening for human relative hand skill, under a parent-of-origin model, within four candidate genes close to or within 6 mb of a peak of paternal-specific linkage on 2p12, in a sample of sib pairs recruited for the presence of RD.
We found strong geme association with relative hand skill implicating the gene LRRTM1 leucine-rich repeat transmembrane neuronal 1 and a region of 80 kb upstream of this gene which is located within an intron of CTNNA2. We did not find this association in a sample of normal twin-based sibships from Australia.
LRRTM1 leucine rich repeat transmembrane neuronal 1 [ (human)]
However, consistent with our parent-of-origin association data, we went on to show that LRRTM1 is downregulated on the maternally inherited chromosome, and krrtm1 therefore a newly identified imprinted locus in the human genome. This was a specific hypothesis test that requires no statistical adjustment, and indicates that LRRTM1 is a novel susceptibility factor for schizophrenia.
We also found consistent evidence for association in a large case—control sample of European descent that was collected in Scotland and Germany.
The failure to replicate may nonetheless be related to modest power in the Chinese sample of families.
Alternatively, the nonreplication in the Chinese may indicate that the haplotype does not carry risk variation in this population it may also be relevant that native Chinese speakers show some morphological differences to English speakers in language-related areas of the brain A geen study in a larger Chinese sample will be required to distinguish these possibilities, together with identification of the functional variants in European populations.
Of a total of approximately 35 human genes, only roughly 40 were previously known to be lrrtj1, and the total number is unlikely to exceed this greatly. Our data indicate a role for the haplotype in handedness variability and susceptibility to schizophrenia, in European populations, while the data on imprinting are consistent with lrrmt1 paternal-specific nature of this effect. Our data suggest that a subtype of schizophrenia, linked to misregulation of human LRRTM1, may have its origins in fetal neurodevelopment.
Since LRRTM1 appears to underlie the strongest linkage to schizophrenia in the genome, as identified fene a meta-analysis of 20 genomewide linkage scans, 16 it is possible that LRRTM1 dysfunction causes a major, common subtype of schizophrenia. Assessing the frequency of this subtype will require studies in further clinical and epidemiological samples, together with a better definition of the functional genetic and epigenetic variation at the LRRTM1 locus.
This information may have a substantial impact on pharmacogenetic studies and the development of new treatments for schizophrenia, by allowing patient heterogeneity to be accounted for in clinical trial studies. The receptor-like structure of LRRTM1 also suggests that it may be a drug-tractable target in its own right. LRRTM1 is one of a four-member family of type I transmembrane proteins containing leucine-rich repeat LRR domains, lrrmt1 are commonly involved in protein—protein interactions LRRs are present in the Slits and Nogo-receptor, 3435 involved in axonal pathfinding.
Thus, LRRTM1 is an ideal candidate gene for having an involvement in subtle developmental abnormalities of the central nervous system. When comparing expression between human and mouse, it seems that there is a striking absence of signal in caudate and putamen in mouse, at least at e15 and in adult. Also, expression lfrtm1 the fetal human thalamus is more restricted as compared to the lrrttm1, with staining relatively limited to dorsomedial regions that have been implicated in schizophrenia.
However, we genne rule out a subtle asymmetry of function lgrtm1 expression at some restricted time point during human brain development, as for the transcription factor LMO4. Humans have the strongest population-level bias in handedness of any primate, 12 and LRRTM1 is a candidate for having had a role in the evolution of this trait.
There is a high level of discordance in imprinting between humans and mice; 32 the gene Lrrtk1 is an example.
Genomic imprinting can arise when the optimal level of maternal resource investment in offspring differs between the two parental sexes, in polygamous mating systems.