ABSTRACT
A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 × 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies.
Subject(s)
Cognition , Mental Disorders/genetics , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Bipolar Disorder/genetics , DNA Mutational Analysis , Depressive Disorder, Major/genetics , Exons , Family , Gene Frequency , Genetic Predisposition to Disease , Humans , Pedigree , Schizophrenia/genetics , Scotland , White People/geneticsABSTRACT
The serine-threonine kinase AKT1 is a central player in the oncogenic pathway controlled by PI3K. Recently, a somatic mutation in AKT1 (E17K) has been detected in breast, colorectal, lung and ovarian cancers. The E17K change results in constitutive AKT1 activation and induces leukaemia in mice. We determined the occurrence of the E17K variant in a panel of 764 tumour samples. These included breast, lung, ovarian, colorectal and pancreatic carcinomas as well as melanomas and glioblastomas. Despite the fact that these tumours are known to bear alterations in genes involved in the PI3K signalling pathway, AKT1(E17K) was detected only in breast (16/273), colorectal (1/88) and lung (1/155) cancers. Within the neoplasms of breast origin, the AKT1(E17K) variant was mutually exclusive with respect to the PIK3CA(E454K or H1047R) alleles and was present only in ductal and lobular histotypes. Our results, showing that AKT1 mutations seem to occur in a tissue-specific fashion have basic and clinical implications. First, the activity of mutated AKT1 in oncogenic PI3K signalling could be strictly dependent on the cell and tissue milieu. Second, therapeutic efforts aimed at selective targeting the AKT1(E17K) variant could be effective mainly in specific cancer types.
Subject(s)
Mutation , Neoplasms/genetics , Proto-Oncogene Proteins c-akt/genetics , Class I Phosphatidylinositol 3-Kinases , Humans , Organ Specificity , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/physiologyABSTRACT
A yeast two-hybrid screen revealed that regulatory subunits (RII) of PKAII bind the Yotiao protein. Yotiao interacts with the NR1 subunit of the NMDA receptor. A purified C-terminal fragment of Yotiao binds PKAII, via an RII binding site constituted by amino acid residues 1452-1469, with a dissociation constant (K(d)) between 50 and 90 nM in vitro. A stable complex composed of Yotiao, RII and NR1 was immunoprecipitated from whole rat brain extracts. Immunostaining analysis disclosed that Yotiao, RIIbeta and NR1 colocalize in striatal and cerebellar neurons. Co-assembly of Yotiao/PKAII complexes with NR1 subunits may promote cAMP-dependent modulation of NMDA receptor activity at synapses, thereby influencing brain development and synaptic plasticity.
Subject(s)
Adaptor Proteins, Signal Transducing , Carrier Proteins/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Cytoskeletal Proteins/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , A Kinase Anchor Proteins , Amino Acid Sequence , Animals , Carrier Proteins/chemistry , Cytoskeletal Proteins/chemistry , Ligands , Mice , Molecular Sequence Data , Protein Binding , Rats , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Sequence Homology, Amino Acid , Substrate SpecificityABSTRACT
Sixty-four counselors and 32 alternative school teachers in 13 grass-roots agencies reported on levels of participation, influence, and competence in making clinical and administrative decisions. The data supported predictions that (a) professionals would report greater decision-making opportunities and abilities than nonprofessionals, and (b) that workers in general would report higher levels of participation, influence, and competence in clinical than in administrative domains, and higher levels of competence than influence in both domains. However, regression analyses testing the effects of the decision-making variables on different aspects of job satisfaction did not support predicted interactions among participation, influence, and competence. Rather, decision-making involvements had positive effects and decision-making abilities had negative effects on worker morale. The discussion high-lights the need for further research to identify the underlying processes involved in the observed relationships.
