Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet

Department of Genetics, Children's Hospital Boston, Boston, MA 02115, USA.
European Journal of HumanGenetics (Impact Factor: 4.35). 06/2008; 16(5):614-8. DOI: 10.1038/sj.ejhg.5202006
Source: PubMed


Neuroligin 4 (NLGN4) is a member of a cell adhesion protein family that appears to play a role in the maturation and function of neuronal synapses. Mutations in the X-linked NLGN4 gene are a potential cause of autistic spectrum disorders, and mutations have been reported in several patients with autism, Asperger syndrome, and mental retardation. We describe here a family with a wide variation in neuropsychiatric illness associated with a deletion of exons 4, 5, and 6 of NLGN4. The proband is an autistic boy with a motor tic. His brother has Tourette syndrome and attention deficit hyperactivity disorder. Their mother, a carrier, has a learning disorder, anxiety, and depression. This family demonstrates that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms.

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    • "The p.Thr271fs mutation in NLGN1 is found in heterozygosis, suggesting an age-dependent dosage effect in the patient. A dosage effect has been suggested for X-linked NLGN3 and NLGN4 mutations in autism, as male patients inherit NLGN3 or NLGN4 mutations from their unaffected or milder affected mothers (Jamain, et al., 2003; Laumonnier, et al., 2004; Lawson-Yuen, et al., 2008; Yan, et al., 2005). Therefore, it is tempting to speculate that while "
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    ABSTRACT: Neuroligins (NLs) are cell-adhesion proteins that regulate synapse formation and function. Neuroligin 1 (NL1) promotes the formation of glutamatergic synapses and mediates long-term potentiation in mouse models. Thus, altered NL1 function could mediate the synaptic and memory deficits associated with Alzheimer's disease (AD). Here, we describe a frameshift mutation, c.875_876insTT, in the neuroligin 1 gene (NLGN1) in a patient with AD and familial history of AD. The insertion generates a premature stop codon in the extracellular domain of NL1 (p.Thr271fs). Expression of mutant NL1 shows accumulation of truncated NL1 proteins in the endoplasmic reticulum. In hippocampal neurons, the p.Thr271fs mutation abolishes the ability of NL1 to promote the formation of glutamatergic synapses. Our data support a role for inactivating mutations in NLGN1 in AD. Previous studies have reported rare mutations in X-linked NLGNL3 and NLGNL4 genes in patients with autism, which result in the inactivation of the mutant alleles. Therefore, together with a role in neurodevelopmental disorders, altered NL function could underlie the molecular mechanisms associated with brain diseases in the elderly.
    Full-text · Article · Oct 2015 · Neurobiology of Aging
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    • "Subsequently, a different NLGN4X truncating mutation was identified in a multigenerational pedigree with 13 affected males with either non-syndromic ID (10 individuals), ID with ASD, or ASD without ID (Laumonnier et al., 2004). In 2008, another familial NLGN4X truncating mutation was identified in two brothers with TS/motor tic, one with ASD and the other with attention deficit/hyperactivity disorder (ADHD) and a mother carrier with a learning disorder, anxiety, and depression (Lawson-Yuen et al., 2008). This latter NTSC association with TS and ADHD was just the first of many such associations which have emerged since between the NTSC and the divergent behavioral profiles of ASD and TS (Clarke et al., 2012). "
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    ABSTRACT: Autism spectrum disorder (ASD) is characterized by a broad spectrum of behavioral deficits of unknown etiology. ASD associated mutations implicate numerous neurological pathways including a common association with the neurexin trans-synaptic connexus (NTSC) which regulates neuronal cell-adhesion, neuronal circuitry, and neurotransmission. Comparable DNA lesions affecting the NTSC, however, associate with a diversity of behavioral deficits within and without the autism spectrum including a very strong association with Tourette syndrome. The NTSC is comprised of numerous post-synaptic ligands competing for trans-synaptic connection with one of the many different neurexin receptors yet no apparent association exists between specific NTSC molecules/complexes and specific behavioral deficits. Together these findings indicate a fundamental role for NTSC-balance in stabilizing pre-behavioral control. Further molecular and clinical characterization and stratification of ASD and TS on the basis of NTSC status will help elucidate the molecular basis of behavior - and define how the NTSC functions in combination with other molecular determinates to strengthen behavioral control and specify behavioral deficits.
    Full-text · Article · Feb 2014 · Frontiers in Human Neuroscience
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    • "Another example of trans-synaptic signaling being linked to cognitive disease is seen with neurexins and neuroligins, cell-adhesion molecules that are known to regulate synaptic function (Sudhof, 2008). These molecules have been linked with a variety of diseases including autism (Yan et al., 2005; Szatmari et al., 2007; Kim et al., 2008), schizophrenia (Kirov et al., 2008; Walsh et al., 2008), and other neuropsychiatric conditions (Lawson-Yuen et al., 2008; Sudhof, 2008). Intriguingly, neurexins have been found to be necessary for presynaptic homeostatic plasticity at the mammalian NMJ (Sons et al., 2006), providing another possible link between homeostatic plasticity and neuropsychiatric disease. "
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    ABSTRACT: Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases.
    Full-text · Article · Nov 2013 · Frontiers in Cellular Neuroscience
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