Editing Reelin (section)

== Possible pathological role ==

=== Lissencephaly ===
Disruptions of the RELN gene are considered to be the cause of the rare form of [[lissencephaly]] with [[cerebellar hypoplasia]] classed as a [[microlissencephaly]] called [[Norman-Roberts syndrome]].<ref name="liss2000" /><ref name="liss2001" /> The mutations disrupt [[Splicing (genetics)|splicing]] of the RELN [[Messenger RNA|mRNA]] transcript, resulting in low or undetectable amounts of reelin protein. The [[phenotype]] in these patients was characterized by [[hypotonia]], [[ataxia]], and developmental delay, with lack of unsupported sitting and profound mental retardation with little or no language development. Seizures and [[congenital lymphedema]] are also present. A novel [[chromosomal translocation]] causing the syndrome was described in 2007.<ref name="pmid17431900" />

=== Schizophrenia ===
Reduced expression of reelin and its [[Messenger RNA|mRNA]] levels in the brains of [[schizophrenia]] sufferers had been reported in 1998<ref name="szproof1" /> and 2000,<ref name="szproof2" /> and independently confirmed in postmortem studies of the hippocampus,<ref name="szconfirm1" /> [[cerebellum]],<ref name="pmid15560956" /> [[basal ganglia]],<ref name="BDP_basal_ganglia_2007" /> and cerebral cortex.<ref name="szconfirm2" /><ref name="szconfirm3" /> The reduction may reach up to 50% in some brain regions and is coupled with reduced expression of [[GAD-67]] [[enzyme]],<ref name="pmid15560956" /> which catalyses the transition of [[glutamate]] to [[GABA]]. [[Blood test|Blood levels]] of reelin and its [[isoform]]s are also altered in schizophrenia, along with [[mood disorder]]s, according to one study.<ref name="fatemi_blood_reelin" /> Reduced reelin mRNA prefrontal expression in schizophrenia was found to be the most statistically relevant disturbance found in the multicenter study conducted in 14 separate laboratories in 2001 by Stanley Foundation Neuropathology Consortium.<ref name="Knable_2001" />

[[Epigenetics|Epigenetic]] hypermethylation of DNA in schizophrenia patients is proposed as a cause of the reduction,<ref name="hypermeth" /><ref name="dong" /> in agreement with the observations dating from the 1960s that administration of [[methionine]] to schizophrenic patients results in a profound exacerbation of schizophrenia symptoms in sixty to seventy percent of patients.<ref name="methionine1" /><ref name="methionine2" /><ref name="methionine3" /><ref name="methionine4" /> The proposed mechanism is a part of the "epigenetic hypothesis for schizophrenia pathophysiology" formulated by a group of scientists in 2008 (D. Grayson; A. Guidotti; [[Erminio Costa|E. Costa]]).<ref name="Schizophrenia Research Forum: Current Hypotheses" /><ref name="pmid19395859" /> A postmortem study comparing a [[DNA methyltransferase]] ([[DNA methyltransferase#DNMT 1|DNMT1]]) and Reelin mRNA expression in cortical layers I and V of schizophrenic patients and normal controls demonstrated that in the layer V both DNMT1 and Reelin levels were normal, while in the layer I DNMT1 was threefold higher, probably leading to the twofold decrease in the Reelin expression.<ref name="epigenetic2007" /> There is evidence that the change is selective, and DNMT1 is overexpressed in reelin-secreting GABAergic neurons but not in their glutamatergic neighbours.<ref name="DNMT_inhibition_GAD67_Reelin_2004" /><ref name="pmid15684088" /> [[Methylation]] inhibitors and [[histone deacetylase]] inhibitors, such as [[valproic acid]], increase reelin mRNA levels,<ref name="valpro" /><ref name="valproicreelin" /><ref name="Mitchell" /> while L-methionine treatment downregulates the phenotypic expression of reelin.<ref name="l-meth" />

One study indicated the upregulation of histone deacetylase HDAC1 in the hippocampi of patients.<ref name="pmid17553960" /> Histone deacetylases suppress gene promoters; hyperacetylation of histones was shown in murine models to demethylate the promoters of both reelin and GAD67.<ref name="Dong_2007" /> DNMT1 inhibitors in animals have been shown to increase the expression of both reelin and GAD67,<ref name="DNMT_inhibition_GAD67_Reelin_2006" /> and both DNMT inhibitors and HDAC inhibitors shown in one study<ref name="pmid19029285" /> to activate both genes with comparable dose- and time-dependence. As one study shows, [[S-adenosyl methionine]] (SAM) concentration in patients' prefrontal cortex is twice as high as in the cortices of non-affected people.<ref name="SAM_and_DNMT1_psychosis_2007" /> SAM, being a methyl group donor necessary for DNMT activity, could further shift epigenetic control of gene expression.{{citation needed|date=January 2016}}

Chromosome region [[7q22]] that harbours the ''RELN'' gene is associated with schizophrenia,<ref name="pmid17684500" /> and the gene itself was associated with the disease in a large study that found the polymorphism [[rs7341475]] to increase the risk of the disease in women, but not in men. The women that have the [[single-nucleotide polymorphism]] (SNP) are about 1.4 times more likely to get ill, according to the study.<ref name="pmid18282107" /> Allelic variations of RELN have also been correlated with working memory, memory and executive functioning in nuclear families where one of the members suffers from schizophrenia.<ref name="pmid17684500" /> The association with working memory was later replicated.<ref name="pmid19922905" /> In one small study, nonsynonymous polymorphism [[Val997Leu]] of the gene was associated with left and right ventricular enlargement in patients.<ref name="pmid19054571" />

One study showed that patients have decreased levels of one of reelin receptors, [[VLDLR]], in the peripheral [[lymphocyte]]s.<ref name="pmid17936586" /> After six months of [[antipsychotic]] therapy the expression went up; according to authors, peripheral VLRLR levels may serve as a reliable peripheral biomarker of schizophrenia.<ref name="pmid17936586" />

Considering the role of reelin in promoting dendritogenesis,<ref name="Niu_2004" /><ref name="pmid18477607" /> suggestions were made that the localized dendritic spine deficit observed in schizophrenia<ref name="pmid18463626" /><ref name="pmid10632234" /> could be in part connected with the downregulation of reelin.<ref name="pmid10725376" /><ref name="pmid11592844" />

Reelin pathway could also be linked to schizophrenia and other psychotic disorders through its interaction with risk genes. One example is the neuronal transcription factor [[NPAS3]], disruption of which is linked to schizophrenia<ref name="Kamnasaran_2003" /> and learning disability. Knockout mice lacking NPAS3 or the similar protein [[NPAS1]] have significantly lower levels of reelin;<ref name="Erbel-Sieler_NPAS3_deficient_mice_2004" /> the precise mechanism behind this is unknown. Another example is the schizophrenia-linked gene [[MTHFR]], with murine knockouts showing decreased levels of reelin in the cerebellum.<ref name="pmid15979267" /> Along the same line, it is worth noting that the gene coding for the subunit [[GRIN2B|NR2B]] that is presumably affected by reelin in the process of NR2B->NR2A developmental change of NMDA receptor composition,<ref name="pmid17881522" /> stands as one of the strongest risk [[Candidate gene|gene candidates]].<ref name="GRIN2B_SZ_GENE_DB" /> Another shared aspect between NR2B and RELN is that they both can be regulated by the [[TBR1]] transcription factor.<ref name="pmid15066269" />

The [[Zygosity|heterozygous]] reeler mouse, which is [[Haploinsufficiency|haploinsufficient]] for the RELN gene, shares several neurochemical and behavioral abnormalities with schizophrenia and bipolar disorder,<ref name="HRM_shared_abnormalities_with_SZ" /> but the exact relevance of these murine behavioral changes to the pathophysiology of schizophrenia remains debatable.<ref name="HRM_not_SZ" />

As previously described, reelin plays a crucial role in modulating early neuroblast migration during brain development. Evidences of altered neural cell positioning in post-mortem schizophrenia patient brains<ref>{{cite journal | vauthors = Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE, Jones EG | title = Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients | journal = Archives of General Psychiatry | volume = 53 | issue = 5 | pages = 425–36 | date = May 1996 | pmid = 8624186 | doi=10.1001/archpsyc.1996.01830050061010}}</ref><ref>{{cite journal | vauthors = Joshi D, Fung SJ, Rothwell A, Weickert CS | title = Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia | journal = Biological Psychiatry | volume = 72 | issue = 9 | pages = 725–33 | date = November 2012 | pmid = 22841514 | doi = 10.1016/j.biopsych.2012.06.021 | s2cid = 8400626 }}</ref> and changes to [[gene regulatory network]]s that control [[cell migration]]<ref name=":1">{{cite journal|vauthors=Matigian N, Abrahamsen G, Sutharsan R, Cook AL, Vitale AM, Nouwens A, Bellette B, An J, Anderson M, Beckhouse AG, Bennebroek M, Cecil R, Chalk AM, Cochrane J, Fan Y, Féron F, McCurdy R, McGrath JJ, Murrell W, Perry C, Raju J, Ravishankar S, Silburn PA, Sutherland GT, Mahler S, Mellick GD, Wood SA, Sue CM, Wells CA, Mackay-Sim A|date=2010|title=Disease-specific, neurosphere-derived cells as models for brain disorders|journal=Disease Models & Mechanisms|volume=3|issue=11–12|pages=785–98|doi=10.1242/dmm.005447|pmid=20699480|doi-access=free|url=https://eprints.gla.ac.uk/85448/1/85448.pdf}}</ref><ref>{{cite journal | vauthors = Topol A, Zhu S, Hartley BJ, English J, Hauberg ME, Tran N, Rittenhouse CA, Simone A, Ruderfer DM, Johnson J, Readhead B, Hadas Y, Gochman PA, Wang YC, Shah H, Cagney G, Rapoport J, Gage FH, Dudley JT, Sklar P, Mattheisen M, Cotter D, Fang G, Brennand KJ | title = Dysregulation of miRNA-9 in a Subset of Schizophrenia Patient-Derived Neural Progenitor Cells | journal = Cell Reports | volume = 15 | issue = 5 | pages = 1024–1036 | date = May 2016 | pmid = 27117414 | pmc = 4856588 | doi = 10.1016/j.celrep.2016.03.090 }}</ref> suggests a potential link between altered reelin expression in patient brain tissue to disrupted cell migration during brain development. To model the role of reelin in the context of schizophrenia at a cellular level, olfactory neurosphere-derived cells were generated from the [[Nose|nasal]] [[Biopsy|biopsies]] of schizophrenia patients, and compared to cells from healthy controls.<ref name=":1" /> Schizophrenia patient-derived cells have reduced levels of reelin mRNA<ref name=":1" /> and protein<ref name=":2">{{cite journal | vauthors = Tee JY, Sutharsan R, Fan Y, Mackay-Sim A | title = Schizophrenia patient-derived olfactory neurosphere-derived cells do not respond to extracellular reelin | journal = npj Schizophrenia | volume = 2 | pages = 16027 | date = 2016 | pmid = 27602387 | pmc = 4994154 | doi = 10.1038/npjschz.2016.27 }}</ref> when compared to healthy control cells, but expresses the key reelin receptors and DAB1 accessory protein.<ref name=":2" /> When grown ''[[in vitro]]'', schizophrenia patient-derived cells were unable to respond to reelin coated onto [[tissue culture]] surfaces; In contrast, cells derived from healthy controls were able to alter their cell migration when exposed to reelin.<ref name=":2" /> This work went on to show that the lack of cell migration response in patient-derived cells were caused by the cell's inability to produce enough [[focal adhesion]]s of the appropriate size when in contact with extracellular reelin.<ref name=":2" /> More research into schizophrenia cell-based models are needed to look at the function of reelin, or lack of, in the pathophysiology of schizophrenia.

=== Bipolar disorder ===
Decrease in RELN expression with concurrent upregulation of [[DNMT1]] is typical of [[bipolar disorder]] with psychosis, but is not characteristic of patients with major depression without psychosis, which could speak of specific association of the change with psychoses.<ref name="szproof2" /> One study suggests that unlike in schizophrenia, such changes are found only in the cortex and do not affect the deeper structures in psychotic bipolar patients, as their basal ganglia were found to have the normal levels of DNMT1 and subsequently both the reelin and GAD67 levels were within the normal range.<ref name="BDP_basal_ganglia_2007" />

In a genetic study conducted in 2009, preliminary evidence requiring further [[DNA replication]] suggested that variation of the RELN [[gene]] (SNP [[rs362719]]) may be associated with susceptibility to [[bipolar disorder]] in women.<ref name="BipWoman09" />

===Autism===
{{main|Heritability of autism}}

[[Autism spectrum|Autism]] is a [[neurodevelopmental disorder]] that is generally believed to be caused by mutations in several locations, likely triggered by environmental factors. The role of reelin in autism is not decided yet.<ref>{{cite journal | vauthors = Lammert DB, Howell BW | title = RELN Mutations in Autism Spectrum Disorder | journal = Frontiers in Cellular Neuroscience | volume = 10 | issue = 84 | pages = 84 | date = 31 March 2016 | pmid = 27064498 | pmc = 4814460 | doi = 10.3389/fncel.2016.00084 | doi-access = free }}</ref>

Reelin was originally in 2001 implicated in a study finding associations between autism and a [[polymorphism (biology)|polymorphic]] GGC/CGG [[repeated sequence (DNA)|repeat]] preceding the 5' ATG initiator codon of the RELN gene in an Italian population. Longer triplet repeats in the 5' region were associated with an increase in autism susceptibility.<ref name="pmid11317216" /> However, another study of 125 multiple-incidence families and 68 single-incidence families from the subsequent year found no significant difference between the length of the polymorphic repeats in affected and controls. Although, using a family based association test larger ''reelin'' alleles were found to be transmitted more frequently than expected to affected children.<ref name="pmid12399956" /> An additional study examining 158 subjects with German lineage likewise found no evidence of triplet repeat polymorphisms associated with autism.<ref name="pmid14515139" /> And a larger study from 2004 consisting of 395 families found no association between autistic subjects and the CGG triplet repeat as well as the allele size when compared to age of first word.<ref name="pmid15048647" />
In 2010 a large study using data from 4 European cohorts would find some evidence for an association between autism and the [[rs362780]] RELN polymorphism.<ref name="pmid20442744"/>

Studies of [[genetically modified organism|transgenic]] mice have been suggestive of an association, but not definitive.<ref name="pmid17919129" />

===Temporal lobe epilepsy: granule cell dispersion===
Decreased reelin expression in the hippocampal tissue samples from patients with [[temporal lobe epilepsy]] was found to be directly correlated with the extent of [[granule cell]] dispersion (GCD), a major feature of the disease that is noted in 45%–73% of patients.<ref name="TLE1" /><ref name="TLE2" /> The dispersion, according to a small study, is associated with the RELN promoter hypermethylation.<ref name="pmid19287316" /> According to one study, prolonged seizures in a rat model of mesial temporal lobe epilepsy have led to the loss of reelin-expressing interneurons and subsequent ectopic chain migration and aberrant integration of newborn dentate granule cells. Without reelin, the chain-migrating neuroblasts failed to detach properly.<ref name="Gonq_2007" /> Moreover, in a [[kainate]]-induced mouse epilepsy model, exogenous reelin had prevented GCD, according to one study.<ref name="pmid19185570" />

===Alzheimer's disease===
The Reelin receptors [[ApoER2]] and [[VLDLR]] belong to the [[LDL]] receptor gene family.<ref name="pmid11252768" /> All members of this family are receptors for [[Apolipoprotein E]] (ApoE). Therefore, they are often synonymously referred to as 'ApoE receptors'. ApoE occurs in 3 common isoforms (E2, E3, E4) in the human population. [[ApoE4]] is the primary genetic risk factor for late-onset [[Alzheimer's disease]]. This strong genetic association has led to the proposal that ApoE receptors play a central role in the pathogenesis of Alzheimer's disease.<ref name="pmid11252768" /><ref name="pmid17053810" /> According to one study, reelin expression and [[glycosylation]] patterns are altered in [[Alzheimer's disease]]. In the cortex of the patients, reelin levels were 40% higher compared with controls, but the cerebellar levels of the protein remain normal in the same patients.<ref name="alz" /> This finding is in agreement with an earlier study showing the presence of Reelin associated with amyloid plaques in a transgenic AD mouse model.<ref name="alzmouse" /> A large genetic study of 2008 showed that RELN gene variation is associated with an increased risk of Alzheimer's disease in women.<ref name="pmid18599960" /> The number of reelin-producing Cajal-Retzius cells is significantly decreased in the first cortical layer of patients.<ref name="pmid16051543" /><ref name="pmid17453452" /> Reelin has been shown to interact with [[amyloid precursor protein]],<ref name="pmid19515914" /> and, according to one in-vitro study, is able to counteract the Aβ-induced dampening of [[NMDA-receptor]] activity.<ref name="Herz2009relnabeta" /> This is modulated by ApoE isoforms, which selectively alter the recycling of ApoER2 as well as AMPA and NMDA receptors.<ref name="pmid20547867" />

=== Cancer ===
[[DNA methylation]] patterns are often changed in tumours, and the RELN gene could be affected: according to one study, in the [[pancreatic cancer]] the expression is suppressed, along with other reelin pathway components<ref name="Pancreatic_Cancer_2006" /> In the same study, cutting the reelin pathway in cancer cells that still expressed reelin resulted in increased motility and invasiveness. On the contrary, in [[prostate cancer]] the RELN expression is excessive and correlates with [[Gleason score]].<ref name="Prostate_Cancer_2007_1" /> [[Retinoblastoma]] presents another example of RELN overexpression.<ref name="pmid17615543" /> This gene has also been seen recurrently mutated in cases of [[acute lymphoblastic leukaemia]].<ref name="doi.10.1038/nature10725">{{cite journal | vauthors = Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG | title = The genetic basis of early T-cell precursor acute lymphoblastic leukaemia | journal = Nature | volume = 481 | issue = 7380 | pages = 157–63 | date = January 2012 | pmid = 22237106 | pmc = 3267575 | doi = 10.1038/nature10725 | bibcode = 2012Natur.481..157Z }}</ref>

=== Other conditions ===
One [[genome-wide association study]] indicates a possible role for RELN gene variation in [[otosclerosis]], an abnormal growth of bone of the [[middle ear]].<ref name="pmid19230858" /> In a statistical search for the genes that are differentially expressed in the brains of cerebral malaria-resistant versus cerebral malaria-susceptible mice, Delahaye et al. detected a significant upregulation of both RELN and [[DAB1]] and speculated on possible protective effects of such over-expression.<ref name="pmid18062806" /> In 2020, a study reported a novel variant in ''RELN'' gene (S2486G) which was associated with [[ankylosing spondylitis]] in a large family. This suggested a potential insight into the pathophysiological involvement of reelin via inflammation and osteogenesis pathways in ankylosing spondylitis, and it could broaden the horizon toward new therapeutic strategies.<ref>{{cite journal | vauthors = Garshasbi M, Mahmoudi M, Razmara E, Vojdanian M, Aslani S, Farhadi E, Jensen LR, Arzaghi SM, Poursani S, Bitaraf A, Eidi M, Gharehdaghi EE, Kuss AW, Jamshidi A | title = Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS | journal = European Journal of Human Genetics | volume = 28 | issue = 6 | pages = 754–762 | date = June 2020 | pmid = 32001840 | pmc = 7253431 | doi = 10.1038/s41431-020-0573-4 }}</ref> A 2020 study from UT Southwestern Medical Center suggests circulating Reelin levels might correlate with MS severity and stages, and that lowering Reelin levels might be a novel way to treat MS.<ref>{{Cite web|url=https://neurosciencenews.com/reelin-multiple-sclerosis-16819/|title = 'Reelin' in a New Treatment for Multiple Sclerosis|date = 12 August 2020}}</ref>