Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia

Abstract

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).

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

“…Although the precise mechanism governing synaptic adhesion between Slitrks and LAR-RPTPs remains elusive, the fact that Slitrks and LAR-RPTPs serve double duty as inducers of either excitatory or inhibitory synapses places these protein families at center stage in the control of excitatory-inhibitory balance, which is critical for neuronal function (34). Indeed, genetic mutations of a subset of Slitrks have been associated with multiple neuropsychiatric diseases (7,9,10). In support of this idea, Slitrk1 is expressed in neural circuits of basal ganglia implicated in Tourette syndrome (35).…”

“…Intriguingly, Slitrk isoforms have been associated with multiple neuropsychiatric disorders. For example, Slitrk1 variants are linked to the spectrum of obsessive-compulsive disorders (OCDs), Tourette syndrome, and trichotillomania (7,8), and Slitrk2 is associated with schizophrenia and bipolar disorder (9,10). Moreover, Slitrk1 mutant mice show anxiety-like behaviors and Slitrk5-deficient mice display OCD-like behaviors (11,12).…”

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…These animals also exhibit a decreased adult neurogenesis. Treatment of Finally, rare missense variants in OPHN1 gene have been identified in patients with ASD 206,266 .…”

20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition

“…[7][8][9] Despite the extensive attention given to these early reports, and early attempts at replication, by screening for MAOA deficiency in cohorts of patients with ID and/or abnormal behavior, 10 no other clearly pathogenic mutation in MAOA was reported to our knowledge in other patients in the past 20 years, 11 with the possible exception of a missense variant predicted to be damaging reported in a single patient with autism spectrum disorder (ASD). 12 Many association studies investigated the potential role of MAOA in risk of abnormal behaviors, focusing on a 'variable number of tandem repeats' (VNTR) polymorphism 13 located in the MAOA promoter region, whose alleles are associated with variations of transcriptional activity, with a 'low' and a 'high' activity frequent alleles. Notably, Caspi et al 14 reported that maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems.…”