Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders. S chizophrenia (SCZ) is a chronic psychiatric disorder characterized by a profound disruption in cognition, behavior, and emotion which begins in adolescence or early adulthood. There is significant clinical variability among SCZ patients, suggesting that it is etiologically heterogeneous. There are several hypotheses to explain genetic factors underlying SCZ, such as polygenic inheritance (1) or, in a fraction of cases, variably penetrant de novo mutations. The de novo hypothesis is based on several observations. One is that relatives of an individual with SCZ have a higher risk of being affected (parents 6%, offspring 13%, and siblings 9% compared with 1% for the general population) (2). The greater frequency in offspring than in parents may occur if new mutations account for a fraction of SCZ cases. Also, there is a significantly increased risk of SCZ with increasing paternal age (3), which could result from the age-related increase in paternal de novo mutations. Furthermore, despite reduced reproductive fitness (4) and extremely variable environmental factors, the incidence of SCZ is maintained at ∼1% worldwide. Interestingly, recent studies reported de novo copy-number variants in SCZ, providing further support for the de novo mutation hypothesis (5, 6).As part of the Synapse to Disease (S2D) project aimed at exploring the de novo mutation hypothesis in brain diseases, we are sequencing synaptic genes in individuals with SCZ and autism spectrum disorder (ASD), two neurodevelopmental disorders. Recently, mutations in the SHANK3 (SH3 and multiple ankyrin repeat domains 3) gene, encoding a scaffolding protein abundant in the postsynaptic density of excitatory synapses on dendritic spines, were found in patients with ASD (7-9). Considering that ASD and SCZ share some features, we decided to screen the SHANK3 gene in our cohort of SCZ probands. Given our hypothesis that a significant fraction of SCZ cases are the result of new mutations, we selected SCZ cases with unaffected parents and screened for de novo mutations.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified > 200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.

The monocytic leukemia zinc finger protein MOZ and the related factor MORF form tetrameric complexes with ING5 (inhibitor of growth 5), EAF6 (Esa1-associated factor 6 ortholog), and the bromodomain-PHD finger protein BRPF1, -2, or -3. To gain new insights into the structure, function, and regulation of these complexes, we reconstituted them and performed various molecular analyses. We found that BRPF proteins bridge the association of MOZ and MORF with ING5 and EAF6. An N-terminal region of BRPF1 interacts with the acetyltransferases; the enhancer of polycomb (EPc) homology domain in the middle part binds to ING5 and EAF6. The association of BRPF1 with EAF6 is weak, but ING5 increases the affinity. These three proteins form a trimeric core that is conserved from Drosophila melanogaster to humans, although authentic orthologs of The gene of MOZ (monocytic leukemia zinc finger protein, also referred to as MYST3 and KAT6A), located on chromosome 8p11, was first identified as a fusion partner in chromosome translocation t(8;16)(p11;p13) (2, 52). This recurrent translocation is associated with a monocytic subtype of acute myeloid leukemia and results in the fusion of the MOZ Nterminal domain to the C-terminal part of the transcription coactivator CBP. Two other leukemia-associated chromosomal rearrangements lead to the expression of proteins fusing MOZ fragments to the CBP paralog p300 and the p300/CBP-interacting nuclear receptor coactivator TIF2 (transcription intermediary factor 2, also known as steroid receptor coactivator 2 [SRC-2] and nuclear receptor coactivator 2 [NCOA2]) (6,8,29,34). One of the resulting fusion proteins, MOZ-TIF2, is known to promote self-renewal of leukemic stem cells (17,25), suggesting that the chromosome abnormalities play a causal role in leukemogenesis. In addition, it was recently reported that MOZ is fused to NCOA3 (22), a TIF2 paralog synonymous with SRC-3 and AIB1 (amplified in breast cancer 1). MOZ is highly homologous to MORF (MOZ-related factors, also named Querkopf, MYST4, and KAT6B) (11,64). The MORF gene is rearranged in leukemia patients with t(10; 16)(q22;p13) (46) and in leiomyoma cases with t(10;17)(p11; q21) (40). The CBP gene is the fusion partner in the former translocation, while the GCN5 gene is a potential candidate in the latter translocation. All of these findings suggest that deregulated acetylation has an important role in oncogenesis. In addition, recent studies indicate that MOZ and MORF play key roles in hematopoiesis, skeletogenesis, neurogenesis, and other developmental processes (16,26,38,39,62,64). Therefore, MOZ and MORF are intimately linked to both normal development and cancer development (63,69).At the molecular level, available data suggest that this pair of paralogs functions as transcriptional coactivators with intrinsic histone acetyltransferase (HAT) activity (3,11,12,27,28,48). Both possess the MYST domain, a catalytic core conserved among members of the MYST family of acetyltransferases (2, 52). Within this family, there are five members in hu...

We describe here the identification and functional characterization of a novel human histone acetyltransferase, termed MORF (monocytic leukemia zinc finger protein-related factor). MORF is a 1781-residue protein displaying significant sequence similarity to MOZ (monocytic leukemia zinc finger protein). MORF is ubiquitously expressed in adult human tissues, and its gene is located at human chromosome band 10q22. MORF has intrinsic histone acetyltransferase activity. In addition to its histone acetyltransferase domain, MORF possesses a strong transcriptional repression domain at its N terminus and a highly potent activation domain at its C terminus. Therefore, MORF is a novel histone acetyltransferase that contains multiple functional domains and may be involved in both positive and negative regulation of transcription.