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Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL -rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4 , MLLT3/AF9 , MLLT1/ENL , MLLT10/AF10 , ELL , partial tandem duplications ( MLL PTDs) and MLLT4/AF6 , respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.

Two types of endogenous cannabinoid-receptor agonists have been identified thus far. They are the ethanolamides of polyunsaturated fatty acids—arachidonoyl ethanolamide (anandamide) is the best known compound in the amide series—and 2-arachidonoyl glycerol, the only known endocannabinoid in the ester series. We report now an example of a third, ether-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), isolated from porcine brain. The structure of noladin ether was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by comparison with a synthetic sample. It binds to the CB 1 cannabinoid receptor ( K i = 21.2 ± 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds weakly to the CB 2 receptor ( K i > 3 μM).

We introduce an experimental method based upon a glass micropipette microinjection technique for generating a multitude of interconnected vesicles (IVs) in the interior of a single giant unilamellar phospholipid vesicle (GUV) serving as a cell model system. The GUV membrane, consisting of a mixture of soybean polar lipid extract and anionic phosphatidylserine, is adhered to a multilamellar lipid vesicle that functions as a lipid reservoir. Continuous IV formation was achieved by bringing a micropipette in direct contact with the outer GUV surface and subjecting it to a localized stream of a Ca 2+ solution from the micropipette tip. IVs are rapidly and sequentially generated and inserted into the GUV interior and encapsulate portions of the micropipette fluid content. The IVs remain connected to the GUV membrane and are interlinked by short lipid nanotubes and resemble beads on a string. The vesicle chain-growth from the GUV membrane is maintained for as long as there is the supply of membrane material and Ca 2+ solution, and the size of the individual IVs is controlled by the diameter of the micropipette tip. We also demonstrate that the IVs can be co-loaded with high concentrations of neurotransmitter and protein molecules and displaying a steep calcium ion concentration gradient across the membrane. These characteristics are analogous to native secretory vesicles and could, therefore, serve as a model system for studying secretory mechanisms in biological systems.

Bipolar disorder (BD) and schizophrenia are psychiatric disorders that manifest unusual mental, behavioral, and emotional patterns leading to suffering and disability. These disorders span heterogeneous conditions with variable heredity and elusive pathophysiology. Mood stabilizers such as lithium and valproic acid (VPA) have been shown to be effective in BD and, to some extent in schizophrenia. This review highlights the efficacy of lithium and VPA treatment in several randomized, controlled human trials conducted in patients suffering from BD and schizophrenia. Furthermore, we also address the importance of using induced pluripotent stem cells (iPSCs) as a disease model for mirroring the disease’s phenotypes. In BD, iPSC-derived neurons enabled finding an endophenotype of hyperexcitability with increased hyperpolarizations. Some of the disease phenotypes were significantly alleviated by lithium treatment. VPA studies have also reported rescuing the Wnt/β-catenin pathway and reducing activity. Another significant contribution of iPSC models can be attributed to studying the molecular etiologies of schizophrenia such as abnormal differentiation of patient-derived neural stem cells, decreased neuronal connectivity and neurite number, impaired synaptic function, and altered gene expression patterns. Overall, despite significant advances using these novel models, much more work remains to fully understand the mechanisms by which these disorders affect the patients’ brains.

WW domain‐containing oxidoreductase ( WWOX ) is an emerging neural gene‐regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause WWOX‐related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murine Wwox recapitulates phenotypes of Wwox ‐null mice leading to intractable epilepsy, hypomyelination, and postnatal lethality. Here, we designed and produced an adeno‐associated viral vector (AAV9) harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter ( AAV‐SynI‐WWOX ). Testing the efficacy of AAV‐SynI‐WWOX delivery in Wwox ‐null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, myelination deficits, and the premature lethality and behavioral deficits of Wwox ‐null mice. These findings provide a proof‐of‐concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12. SYNOPSIS AAV‐mediated neuronal WWOX restoration reverses abnormal defects of Wwox null mice, providing a proof‐of‐concept for WWOX gene therapy as a promising approach for treating children with WOREE syndrome. Neuronal WWOX restoration improves the overall growth of Wwox null mice. WWOX restoration reduces neuronal hyperexcitability and neuroinflammation. Neuronal WWOX delivery increases myelination, likely by promoting differentiation of OPCs to mature oligodendrocytes. Neuronal restoration of WWOX is associated with normal behavioral and motor functions of the rescued Wwox null mice. Graphical Abstract AAV‐mediated neuronal WWOX restoration reverses abnormal defects of Wwox null mice, providing a proof‐of‐concept for WWOX gene therapy as a promising approach for treating children with WOREE syndrome.

Developmental and epileptic encephalopathies (DEE) are a group of disorders associated with intractable seizures, brain development, and functional abnormalities, and in some cases, premature death. Pathogenic human germline biallelic mutations in tumor suppressor WW domain‐containing oxidoreductase ( WWOX ) are associated with a relatively mild autosomal recessive spinocerebellar ataxia‐12 (SCAR12) and a more severe early infantile WWOX ‐related epileptic encephalopathy (WOREE). In this study, we generated an in vitro model for DEEs, using the devastating WOREE syndrome as a prototype, by establishing brain organoids from CRISPR‐engineered human ES cells and from patient‐derived iPSCs. Using these models, we discovered dramatic cellular and molecular CNS abnormalities, including neural population changes, cortical differentiation malfunctions, and Wnt pathway and DNA damage response impairment. Furthermore, we provide a proof of concept that ectopic WWOX expression could potentially rescue these phenotypes. Our findings underscore the utility of modeling childhood epileptic encephalopathies using brain organoids and their use as a unique platform to test possible therapeutic intervention strategies. SYNOPSIS Mutations in the human WWOX gene cause devastating developmental and neurological diseases in young children called WOREE syndrome and SCAR12 syndrome. Using both gene editing and reprogramming technologies these maladies can now be modeled in human brain organoids, allowing for molecular and electrophysiological study of the pathology, together with testing possible therapeutic interventions. At early stages of development WWOX is highly expressed in neural stem cells called ventricular radial glia (vRGs). WWOX ‐mutated brain organoids have imbalanced levels of excitatory and inhibitory neurons and are hyperexcitable, demonstrating epileptiform activity upon electrophysiological recordings. WWOX mutations cause increased astrogenesis and cortical dysplasia. WOREE‐modeled organoids have impaired DNA damage response and chronic activation of the Wnt‐signaling pathway. WWOX gene reintroduction could benefit patients suffering from WWOX mutations. Graphical Abstract Mutations in the human WWOX gene cause devastating developmental and neurological diseases in young children called WOREE syndrome and SCAR12 syndrome. Using both gene editing and reprogramming technologies these maladies can now be modeled in human brain organoids, allowing for molecular and electrophysiological study of the pathology, together with testing possible therapeutic interventions.

Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.

The genetics of autism The autism spectrum disorders (ASDs) are a group of conditions typically characterized by repetitive behaviour, severely restricted interests and difficulties with social interactions and communication. ASDs are highly heritable, yet the underlying genetic determinants remain largely unknown. A genome-wide analysis reveals that people with ASDs carry a higher load of rare copy-number variants — segments of DNA for which the copy number differs between individual genomes — which are either inherited or arise de novo . The results implicate several novel genes as ASD candidates and point to the importance of cellular proliferation, projection and motility as well as specific signalling pathways in this disorder. The autistic spectrum disorders (ASDs) are highly heritable, yet the underlying genetic determinants remain largely unknown. Here, a genome-wide analysis of rare copy number variants (CNVs) has been carried out, revealing that ASD sufferers carry a higher load of rare, genic CNVs than do controls. Many of these CNVs are de novo and inherited. The results implicate several novel genes in ASDs, and point to the importance of cellular proliferation, projection and motility, as well as specific signalling pathways, in these disorders. The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours 1 . Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability 2 . Although ASDs are known to be highly heritable (∼90%) 3 , the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10 -4 ). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1 , DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.