Neurocognitive impairments and neuropsychiatric risk in 22q11 deletion syndrome

22q11 Deletion Syndrome (22q11DS) is associated with somatic anomalies, learning disability, and psychiatric disturbance; a high rate of schizophrenia (10-40%) has been reported in affected adults. The aim of this study was to acquire evidence for genetic disruption of specific developmental processes that may explain the later emergence of psychotic illness in 22q11DS. Neurobiological traits associated with risk for psychosis (endophenotypes) were selected for investigation following review of the existing literature on genetics, neurodevelopment and schizophrenia, and were investigated using cognitive and EEG event-related potential (ERP) methodologies. Adolescents and young adults with 22q11DS were compared to age- and IQ-matched controls on all measures. Between-groups analysis revealed abnormalities of auditory processing, working memory and expressive language in 22q11DS. ERPs provided strong evidence for schizophrenia-like disruption; mismatch negativity (MMN), an ERP elicited by any discriminable change in a repetitive auditory sequence, was reduced in amplitude at frontal electrodes but not at temporal sites. Anomalous context-dependence of speech MMN was also observed; individuals with 22q11DS displayed a specific deficit in eliciting MMN in response to voicing contrasts between speech sounds. No such deficits were found in children with Specific Language Impairment, although other abnormalities in auditory processing were apparent. Within-group analysis indicated that abnormal auditory ERPs were associated with psychiatric symptoms akin to schizotypal personality disorder in some 22q11DS individuals. The association between these impairments supports the view that MMN indexes neurophysio logical processes relevant to psychotic illness. The severity of neurocognitive abnormalities in 22q11DS was found to be modulated by the catechol-o- methyl transferase met 158 val polymorphism on the single non-deleted chromosome 22. Functional variants of the COMT gene have been associated with risk for schizophrenia and schizophrenia-like cognitive abnormalities in the general population. Thus developmental dysregulation of catecholamine systems may at least partially explain the association between 22q11DS and psychosis

Genetic manipulations for targeted gene disruption and complementation.

<p>(A) A scheme representation of the in-frame deletion mutant by double homologous recombination. (B) Plasmid map of the <i>Streptomyces</i> integrative vector, pSET152 for expression of target genes under the control of strong constitutive promoter, <i>ermE*</i>.</p

MOESM1 of Heterologous expression of pikromycin biosynthetic gene cluster using Streptomyces artificial chromosome system

Additional file 1: Figure S1. (A) Confirmation of HindIII insertion near pikRII with apr R check primers shown in Table 2. The expected amplicon size of mutant and wildtype is 1.5kb and 360bp, respectively.; lane 1, 100 bp loading DNA ladder (DYNEBIO Inc.); lane 2 and 4, PCR products from S. venezuelae tDNA; lane 3 and 5, PCR products from S. venezuelae Hindbac tDNA; lane 4 and 5, HindIII digested PCR products. (B) Confirmation of integration of pSAPDK in the vicinity of pikD; lane 1, 1 kb DNA ladder (cosmogenetech); lane 2, PCR product from S. venezuelae Hindbac tDNA; lane 3, PCR product from S. venezuelae tDNA

Amino acid sequence alignment and mutagenesis of NppY.

<p>(A) Amino acid sequence alignment between NppDI and NppY glycosyltransferases in NPP biosynthesis. Regions for mutagenesis are marked; crosshatch, site-directed mutagenesis (dark gray); asterisk, addition of 7 consecutive amino acids (FARSYTP) from NppDI (light gray); arrow, N-terminal of NppY and C-terminal of NppDI were combined based on straight line. (B) NPP conversion rate through expression of various modified <i>nppY</i> genes in ESK6011.</p

Chemical structures of nystatin A1 and NPP.

<p>These structurally related compounds share the same aglycone with mono-sugar, mycosamine. NPP include additional sugar moiety, N-acetylglucosamine.</p

A proposed post-PKS modification pathway in the NPP biosynthesis.

<p>A proposed post-PKS modification pathway in the NPP biosynthesis.</p

Bacterial strains and plasmids used in this study.

<p>^aKm^r, kanamycin resistance; Cm^r, chloramphenicol resistance; Am^r, ampicillin resistance; Apr^r, apramycin resistance; Hyg^r, hygromycin resistance.</p><p>Bacterial strains and plasmids used in this study.</p