BACKGROUND: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3. METHODS: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. RESULTS: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). CONCLUSIONS: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC.

• MeSH
• Child MeSH
• Adult MeSH
• Down-Regulation MeSH
• Infant MeSH
• Contactins * genetics   metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Brain metabolism   MeSH
• Infant, Newborn MeSH
• Autism Spectrum Disorder complications   metabolism   MeSH
• Child, Preschool MeSH
• Tuberous Sclerosis * complications   metabolism   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Previous studies have described the clinical, serological and pathological features of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and antibodies directed against the paranodal proteins neurofascin-155, contactin-1 (CNTN1), contactin-associated protein-1 (Caspr1), or nodal forms of neurofascin. Such antibodies are useful for diagnosis and potentially treatment selection. However, antibodies targeting Caspr1 only or the Caspr1/CNTN1 complex have been reported in few patients with CIDP. Moreover, it is unclear if these patients belong to the same pathophysiological subgroup. Using cell-based assays in routine clinical testing, we identified sera from patients with CIDP showing strong membrane reactivity when both CNTN1 and Caspr1 were co-transfected (but not when CNTN1 was transfected alone). Fifteen patients (10 male; aged between 40 and 75) with antibodies targeting Caspr1/CNTN1 co-transfected cells were enrolled for characterization. The prevalence of anti-Caspr1/CNTN1 antibodies was 1.9% (1/52) in the Sant Pau CIDP cohort, and 4.3% (1/23) in a German cohort of acute-onset CIDP. All patients fulfilled European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite diagnostic criteria for CIDP. Seven (47%) were initially diagnosed with Guillain-Barré syndrome due to an acute-subacute onset. Six (40%) patients had cranial nerve involvement, eight (53%) reported neuropathic pain and 12 (80%) ataxia. Axonal involvement and acute denervation were frequent in electrophysiological studies. Complete response to intravenous immunoglobulin was not observed, while most (90%) responded well to rituximab. Enzyme-linked immunosorbent assay (ELISA) and teased nerve fibre immunohistochemistry confirmed reactivity against the paranodal Caspr1/CNTN1 complex. Weaker reactivity against Caspr1 transfected alone was also detected in 10/15 (67%). Sera from 13 of these patients were available for testing by ELISA. All 13 samples reacted against Caspr1 by ELISA and this reactivity was enhanced when CNTN1 was added to the Caspr1 ELISA. IgG subclasses were also investigated by ELISA. IgG4 was the predominant subclass in 10 patients, while IgG3 was predominant in other three patients. In conclusion, patients with antibodies to the Caspr1/CNTN1 complex display similar serological and clinical features and constitute a single subgroup within the CIDP syndrome. These antibodies likely target Caspr1 primarily and are detected with Caspr1-only ELISA, but reactivity is optimal when CNTN1 is added to Caspr1 in cell-based assays and ELISA.

• MeSH
• Autoantigens immunology   MeSH
• Autoantibodies immunology   MeSH
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating immunology   MeSH
• Adult MeSH
• Contactin 1 immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Cell Adhesion Molecules, Neuronal immunology   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics   MeSH
• Asymptomatic Diseases MeSH
• Genome-Wide Association Study MeSH
• Gout blood   genetics   MeSH
• Adult MeSH
• Genetic Loci genetics   MeSH
• Genotyping Techniques MeSH
• Hyperuricemia genetics   MeSH
• Contactins genetics   MeSH
• Uric Acid blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs genetics   MeSH
• Aldehyde Dehydrogenase, Mitochondrial genetics   MeSH
• Neoplasm Proteins genetics   MeSH
• Glucose Transport Proteins, Facilitative genetics   MeSH
• Risk Factors MeSH
• Zinc Fingers genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Research Support, Non-U.S. Gov't MeSH

The corpus callosum is the brain's largest commissural fiber tract and is crucial for interhemispheric integration of neural information. Despite the high relevance of the corpus callosum for several cognitive systems, the molecular determinants of callosal microstructure are largely unknown. Recently, it was shown that genetic variations in the myelin-related proteolipid 1 gene PLP1 and the axon guidance related contactin 1 gene CNTN1 were associated with differences in interhemispheric integration at the behavioral level. Here, we used an innovative new diffusion neuroimaging technique called neurite orientation dispersion and density imaging (NODDI) to quantify axonal morphology in subsections of the corpus callosum and link them to genetic variation in PLP1 and CNTN1. In a cohort of 263 healthy human adults, we found that polymorphisms in both PLP1 and CNTN1 were significantly associated with callosal microstructure. Importantly, we found a double dissociation between gene function and neuroimaging variables. Our results suggest that genetic variation in the myelin-related gene PLP1 impacts white matter microstructure in the corpus callosum, possibly by affecting myelin structure. In contrast, genetic variation in the axon guidance related gene CNTN1 impacts axon density in the corpus callosum. These findings suggest that PLP1 and CNTN1 gene variations modulate specific aspects of callosal microstructure that are in line with their gene function.

• MeSH
• White Matter anatomy & histology   MeSH
• Corpus Callosum anatomy & histology   MeSH
• Diffusion Magnetic Resonance Imaging methods   MeSH
• Adult MeSH
• Genotype MeSH
• Polymorphism, Single Nucleotide MeSH
• Contactin 1 genetics   physiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Myelin Sheath genetics   MeSH
• Myelin Proteolipid Protein genetics   physiology   MeSH
• Neurites * MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Contactin-associated protein-like 2 (CNTNAP2) encodes for CASPR2, a multidomain single transmembrane protein belonging to the neurexin superfamily that has been implicated in a broad range of human phenotypes including autism and language impairment. Using a combination of biophysical techniques, including small angle x-ray scattering, single particle electron microscopy, analytical ultracentrifugation, and bio-layer interferometry, we present novel structural and functional data that relate the architecture of the extracellular domain of CASPR2 to a previously unknown ligand, Contactin1 (CNTN1). Structurally, CASPR2 is highly glycosylated and has an overall compact architecture. Functionally, we show that CASPR2 associates with micromolar affinity with CNTN1 but, under the same conditions, it does not interact with any of the other members of the contactin family. Moreover, by using dissociated hippocampal neurons we show that microbeads loaded with CASPR2, but not with a deletion mutant, co-localize with transfected CNTN1, suggesting that CNTN1 is an endogenous ligand for CASPR2. These data provide novel insights into the structure and function of CASPR2, suggesting a complex role of CASPR2 in the nervous system.

• MeSH
• X-Ray Diffraction MeSH
• HEK293 Cells MeSH
• Hippocampus cytology   metabolism   MeSH
• Contactin 1 metabolism   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Scattering, Small Angle MeSH
• Protein Interaction Maps MeSH
• Membrane Proteins chemistry   metabolism   ultrastructure   MeSH
• Models, Molecular MeSH
• Mice, Inbred C57BL MeSH
• Nerve Tissue Proteins chemistry   metabolism   ultrastructure   MeSH
• Protein Structure, Tertiary MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH