A current view on contactin-4, -5, and -6: Implications in neurodevelopmental disorders

Oguro-Ando, Asami; Zuko, Amila; Kleijer, Kristel T E; Burbach, J. Peter H.

doi:10.1016/j.mcn.2016.12.004

Cited by 75 publications

(68 citation statements)

References 113 publications

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“…Contactins are members of the L1 immunoglobulin superfamily of proteins, and Cntn6 serves multiple functions in the developing mouse nervous system including orientation of apical dendrites in cortical pyramidal neurons, regulation of Purkinje cell development and synaptogenesis, and oligodendrocyte differentiation from neuroprogenitor cells (Oguro-Ando et al, 2017). Mice with homozygous inactivation of Cntn6 also exhibit reproducible motor impairment (Huang et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Huang

Davis

et al. 2017

Neuron

153

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SUMMARY Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (<1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (>1 Mb), singleton events (OR=2.28, 95%CI [1.39–3.79], p=1.2×10−3) and known, pathogenic CNVs (OR=3.03 [1.85–5.07], p=1.5×10−5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR=20.3, 95%CI [2.6–156.2]; CNTN6 duplications, OR=10.1, 95% CI [2.3–45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

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Section: Discussionmentioning

confidence: 99%

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Huang

Davis

et al. 2017

Neuron

153

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“…All three genes have previously been associated with psychiatric or neurodevelopmental disorders (Supplementary Information: GRM5, PDE4D and CNTN5). PDE4D is a direct protein-protein interactor of DISC1 [54,55], GRM5 modulates glutamatergic signalling, and CNTN5 is a neurodevelopmental gene implicated in the specification of dendritic arbors [56,57]. In the family, it is not possible to separate the direct effects of the translocation and the linked loci on the derived chromosomes.…”

Section: Discussionmentioning

confidence: 99%

DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

et al. 2018

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Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome-and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.

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“…In contrast, the Cntn6 mRNA level in the cerebellum and the hippocampus increases until the adulthood (Lee et al., ). Plenty of studies using null mutant mice indicate that Cntn6 plays key roles in the developing and mature mouse brains (Mercati et al., ; Oguro‐Ando et al., ; Shimoda & Watanabe, ). In the visual cortex of one‐month‐old Cntn6 −/− mice, alterations in the orientation of apical dendrites of pyramidal neurons in layer V was observed (Ye et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…CNTN6 contains six N-terminal Ig-like and four fibronectin type III-like (FNIII) domains and tethers to the cell membrane via a C-terminal glycosylphosphatidylinositol (GPI)-anchor (Maness & Schachner, 2007;Shimoda & Watanabe, 2009;Zuko et al, 2013). Cntn6 has been identified as a candidate risk gene of multiple psychiatric disorders including autism spectrum disorders (ASDs), schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, intellectual disability, and Tourette syndrome (Guo et al, 2012;Hu et al, 2015;Huang et al, 2017;Kashevarova et al, 2014;Kerner, Lambert, & Muthen, 2011;Nava et al, 2014;Oguro-Ando, Zuko, Kleijer, & Burbach, 2017;Okbay et al, 2016;Pinto et al, 2010;Van Daalen et al, 2011), suggesting the necessity of CNTN6 in neural development.…”

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confidence: 99%

Cntn6 deficiency impairs allocentric navigation in mice

Zhao

et al. 2018

Brain and Behavior

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Introduction CNTN6 is an immunoglobulin domain‐containing cell adhesion molecule that belongs to the contactin family. It is involved in the development of the nervous system. We aim to determine the effect of Cntn6 deficiency on the allocentric navigation in mice.MethodsWe recorded the travel distance and escape time of wild‐type and Cntn6 mutant male and female mice in the Morris water maze task according to the protocol.ResultsThere was hardly any Cntn6 expression in the hippocampus of postnatal day 0 (P0) mice, while obvious Cntn6 expression was present in the hippocampal CA1 region of the P7 mice. During the acquisition period of Morris water maze task (Day 1 to 4), Cntn6 −/− male mice failed to shorten the escape time to reach platform on the third day, while the travel distance to platform was not significantly different. There was no significant difference in both escape time and travel distance to the platform among all female subjects. In the probe trial test (Day 5), spatial memory of the female mutant mice was mildly affected, while Cntn6 −/− male mice were normal. In the spatial relearning test (Day 7 to 10), Cntn6 −/− male mice showed no difference in escape time to the platform compared to the wild‐type male mice, while Cntn6 deficient female mice required shorter escape time to travel to the platform on day 7, day 8, and day 10.Conclusions Cntn6 is expressed in the developing hippocampus in mice. Cntn6 deficiency affects spatial learning and memory, indicating that Cntn6 plays a role in the development of hippocampus and affects allocentric navigation of the animals.

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A current view on contactin-4, -5, and -6: Implications in neurodevelopmental disorders

Cited by 75 publications

References 113 publications

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

Rare Copy Number Variants in NRXN1 and CNTN6 Increase Risk for Tourette Syndrome

DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

Cntn6 deficiency impairs allocentric navigation in mice

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