| DLL4 |
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| 1 | | Schizophr. Res. 2005 Jun 75: 1-3 |
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| PMID | 15820317 |
| Title | No causative DLL4 mutations in periodic catatonia patients from 15q15 linked families. |
| Abstract | Two well-supported theories of schizophrenia pathogenesis are the neurotransmitter theory and the neurodevelopmental theory, suggesting, respectively, that dysregulation of neurotransmitter signaling and abnormal brain development are causative in this disease. The strongest evidence of neurotransmitter involvement are suggestions of abnormal dopamine signaling in the prefrontal cortex and one of the strongest indications of developmental abnormalities contributing to this disease is an inverse layering of the prefrontal cortex. These two theories of schizophrenia pathogenesis can be united by their involvement of the prefrontal cortex, where structural abnormalities could lead to neurochemical abnormalities. Accordingly, any gene expressed in the prefrontal cortex of developing brains is a functional candidate for schizophrenia. We have previously reported strong linkage to 15q15 (LOD = 3. 57; P = 2.6 x 10(-5)) in a collection of German multiplex families segregating the periodic catatonia subtype of schizophrenia in a nearly Mendelian fashion. A gene within our 15q15 linkage region, DLL4, is expressed in developing forebrain and produces a NOTCH4 ligand. Variants of NOTCH4 are associated with schizophrenia, thus DLL4 is both a functional as well as a positional candidate for schizophrenia. We screened this gene for mutations in three affected individuals and two unrelated controls and found two previously unreported SNPs, one non-synonymous polymorphism that changed an arganine to a histadine in Exon 7 and one synonymous polymorphism in exons. The non-synonymous SNP is a rare variant in that it was not found in 100 control chromosomes; however, it did not cosegregate with the disease in the extended family so it is not causative in this pedigree. It is unlikely that mutations in DLL4 are causative in this collection of families with linkage to 15q15. |
| SCZ Keywords | schizophrenia,schizophrenic |
| 2 | | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jan 159B: 77-86 |
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| PMID | 22162401 |
| Title | Evaluation of conserved and ultra-conserved non-genic sequences in chromosome 15q15-linked periodic catatonia. |
| Abstract | Conserved and ultra-conserved non-genic sequence elements (CNGs, UCEs) between human and other mammalian genomes seem to constitute a heterogeneous group of functional sequences which likely have important biological function. To determine whether variation in CNGs and UCEs contributes to risk for the schizophrenic subphenotype of periodic catatonia (according to K. Leonhard; OMIM 605419), we evaluated non-coding elements at a critical 7.35?Mb interval on chromosome 15q15 in 8 unrelated cases with periodic catatonia (derived from pedigrees compatible with linkage to chromosome 15q15) and 8 controls, followed by association studies in a cohort of 510 cases and controls. Among 65 CNGs (?100?bp, 100% identity; human-mouse comparison), 7 CNGs matched criteria for UCE (?200? bp, 100% identity). A hot spot of 62/65 CNGs (95%) appeared at the MEIS2 locus, which implicates functional importance of associated (ultra-)conserved elements to this early developmental gene, which is present in the human fetal neocortex and associated with metabolic side effects to antipsychotic drugs. Further CNGs were identified at the PLCB2 and DLL4 locus or located intergenic between TYRO3 and MAPKBP1. Automated sequencing revealed genetic variation in 12.3% of CNGs, but frequencies were low (MAF: 0.06-0.4) in cases. Three variants located inside CNGs/UCEs were found in cases only. In a case-control association study we could not confirm a significant association of these three CNG-variants with periodic catatonia. Our results suggest genetic variation in (ultra-)conserved non-genic sequence elements which might alter functional properties. The identified variants are genetically not associated with the phenotype of periodic catatonia. |
| SCZ Keywords | schizophrenia,schizophrenic |
