What we Can Learn from Neuroligin Gene Mutations and Autism Spectrum Disorders?

The development of the human brain is a complex process that relies on the spatially and timely coordinated actions of genetic and environmental factors as well as experiential influences. Any alterations occurring during such developmental period can lead to various neuro-developmental disorders, being attention deficit hyperactivity disorder (ADHD), intellectual disability (ID) and autism spectrum disorders (ASD) the most common neuro-developmental abnormalities observed in childhood [1,2]. In particular ASD, estimated to affect up to ~1 in 110 children and being 4 times more frequent in males than females [3], encompasses a group of heterogeneous neuro-developmental diseases characterized by a very early onset of dysfunction in socialization (interaction, communication), restricted pattern of interests and stereotyped and repetitive behaviors. In some cases ASD is also associated with intellectual disability and mental retardation of variable degree of severity as well as epilepsy, anxiety, motor deficits and sleep abnormalities [4]. Even though it is now clear that ASD derives from a complex concurrence of genetics, epigenetic and environment factors, its genetic etiology is clearly recognized [5]. Monozygous twins and affected family studies demonstrate that genetic heritability contributes as much as 80– 90% to the occurrence of autistic disorders. Large-scale genetic studies identified almost over a thousand genes associated with ASD and since autism is a spectrum of disorders it is conceivable that, in most cases, different genes act in concert to determine each patient’s specific clinical manifestations [6]. Interestingly, many of the risk-genes identified in non-syndromic ASD cases are involved in various aspects of synapse development (formation and elimination), function and plasticity [7]. Mutations in genes coding for synaptic cell adhesion molecules, scaffolding proteins, and signaling adaptors such as Neuroligins (NLGN); Neurexins (NRXN), synaptic Ras GTPase-activating protein 1 (SYNGAP1); Fragile X Mental Retardation Protein (FMRP), SH3 and multiple ankyrin repeat domains (SHANK 2/3) [8], have been identified in several patients with ASD, to emphasize the concept that synaptic dysfunction at multiple levels may represent one of the major determinant of such brain disorders [9].