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Genetic causes of intellectual disability (ID) include mutations in proteins with various functions. However, many of these proteins are enriched in synapses and recent investigations point out their crucial role in the subtle regulation of synaptic activity and dendritic spine morphogenesis. Moreover, in addition to genetic data, functional and animal model studies are providing compelling evidence that supports the emerging unifying synapse-based theory for cognitive deficit. In this review, we highlight ID-related gene products involved in synaptic morphogenesis and function, with a particular focus on the emergent signaling pathways involved in synaptic plasticity whose disruption results in cognitive deficit.

Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y ) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.

Genetic causes of intellectual disability (ID) include mutations in proteins with various functions. However, many of these proteins are enriched in synapses and recent investigations point out their crucial role in the subtle regulation of synaptic activity and dendritic spine morphogenesis. Moreover, in addition to genetic data, functional and animal model studies are providing compelling evidence that supports the emerging unifying synapse-based theory for cognitive deficit. In this review, we highlight ID-related gene products involved in synaptic morphogenesis and function, with a particular focus on the emergent signaling pathways involved in synaptic plasticity whose disruption results in cognitive deficit.

Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β -catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β -catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β -catenin gene similar to those found in colon cancers and melanomas. These alterations in the β -catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β -catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β -catenin in the nucleus. Thus alterations in the β -catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β -catenin pathway is a major event in the development of HCC in humans and mice.

Intersectin 1 (ITSN1) is a multifunctional adaptor protein which is involved in endocytosis, exocytosis and cellular signaling and it is also associated with such pathologies as Down syndrome and Alzheimer’s disease. The

Primary or nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which affected patients do not have any distinctive clinical or biochemical features in common apart from cognitive impairment 1 . Although it is present in approximately 0.15–0.3% of males 2 , most of the genetic defects associated with MRX, which may involve more than ten different genes, remain unknown 3 . Here we report the characterization of a new gene on the long arm of the X-chromosome (position Xq12) and the identification in unrelated individuals of different mutations that are predicted to cause a loss of function. This gene is highly expressed in fetal brain and encodes a protein of relative molecular mass 91K, named oligophrenin-1, which contains a domain typical of a Rho-GTPase–activating protein (rhoGAP) 4 , 5 . By enhancing their GTPase activity, GAP proteins inactivate small Rho and Ras proteins, so inactivation of rhoGAP proteins might cause constitutive activation of their GTPase targets. Such activation is known to affect cell migration and outgrowth of axons and dendrites in vivo 6 , 7 , 8 ,. Our results demonstrate an association between cognitive impairment and a defect in a signalling pathway that depends on a Ras-like GTPase.

X linked subcortical laminar heterotopia and lissencephaly syndrome (XSCLH/ LIS) is an intriguing disorder of cortical development, which causes classical lissencephaly with severe mental retardation and epilepsy in hemizygous males, and subcortical laminar heterotopia (SCLH) associated with milder mental retardation and epilepsy in heterozygous females. Here we report an exclusion mapping study carried out in three unrelated previously described families in which males are affected with lissencephaly and females with SCLH, using 38 microsatellite markers evenly distributed on the X chromosome. Most of the X chromosome was excluded and potential intervals of assignment in Xq22.3-q23 or in Xq27 are reported. Although the number of informative meioses did not allow a decision between these two loci, it is worth noting that the former interval is compatible with the mapping of a breakpoint involved in a de novo X;autosomal balanced translocation 46,XX,t(X;2)(q22;p25) previously described in a female with classical lissencephaly. In addition, haplotype inheritance in two families showed a grandpaternal origin of the mutation and suggested in one family the presence of mosaicism in germline cells of normal transmitting males.

X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous 1 , 2 , 3 . They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features. At least five MRX genes have been identified by positional cloning, but each accounts for only 0.5%–1.0% of MRX cases 4 , 5 . Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families. RNA in situ hybridization showed that TM4SF2 is highly expressed in the central nervous system, including the cerebral cortex and hippocampus. TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes including β-1 integrins 6 , 7 , 8 . We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth.

Slitrks and their ligands LAR-RPTPs are type I transmembrane proteins previously implicated in the etiology of various neuropsychiatric disorders including obsessive-compulsive disorders (OCDs) and schizophrenia. Over the last decade, their functions were extensively studied in hippocampal neurons in vitro and shown to shape synapse organization. Although both protein families are highly expressed prior to synapse formation, their function in earlier steps of cerebral cortex development remains unknown. Here we investigated the role of Slitrk1, Slitrk2, Slitrk3 and LAR-RPTPs (Ptprs and Ptprd) in the embryonic mouse cortex by acute genetic manipulation using in utero electroporation. All genes, except Slitrk3, promoted specific alterations in radial migration of glutamatergic neurons. Slitrk1 and Slitrk2 overexpression was associated with accumulation of neurons in distinct regions of the cortical plate. Using deletion mutants and a series of Slitrk variants associated with neurodevelopmental disorders (NDDs), we showed that distinct domains are crucial for intracellular Slitrk1 distribution and/or density and shape of VAMP2+ presynaptic boutons. Interestingly, bouton alterations did not correlate with the observed migration delays, suggesting that Slitrk1 influence cell migration independently on its synaptogenic function. Furthermore, co-electroporation experiments with LAR-RPTPs, mimicking their co-expression observed by scRNAseq, rescued the migration deficits, suggesting possible cis-interactions between Slitrks and LAR-RPTPs. Together, these data indicate that in the embryonic cerebral cortex Slitrks and LAR-RPTPs cooperate in consecutive steps of radial migration through distinct mechanisms than in synapse organization and support a relevant role of Slitrk/LAR-RPTP dysfunctions in NDDs at earlier stages of cortical development.

CSTF2 encodes an RNA-binding protein that is essential for mRNA cleavage and polyadenylation (C/P). No disease-associated mutations have been described for this gene. Here, we report a mutation in the RNA recognition motif (RRM) of CSTF2 that changes an aspartic acid at position 50 to alanine (p.D50A), resulting in intellectual disability in male patients. In mice, this mutation was sufficient to alter polyadenylation sites in over 1,000 genes critical for brain development. Using a reporter gene assay, we demonstrated that C/P efficiency of CSTF2D50A was lower than wild type. To account for this, we determined that p.D50A changed locations of amino acid side chains altering RNA binding sites in the RRM. The changes modified the electrostatic potential of the RRM leading to a greater affinity for RNA. These results highlight the importance of 3' end mRNA processing in expression of genes important for brain plasticity and neuronal development.