The engrailed homeobox protein (EN) plays an important role in the regionalization of the neural tube. EN distribution regulates the cerebellum and midbrain morphogenesis, as well as retinotectal synaptogenesis. In humans, the EN1 and EN2 genes code for the EN family of transcription factors. Genetic alterations in the expression of EN2 have been related to different neurologic conditions and more particularly to autism spectrum disorders (ASD). We aimed to study and compare the phenotypes of three series of patients: (1) patients with encephalic structural anomalies (ESA) and abnormalities in the genomic (DNA) and/or transcriptomic (RNAm) of EN2 (EN2-g), (2) ESA patients having other gene mutations (OG-g), and (3) ESA patients free of these mutations (NM-g).Subjects and Methods: We have performed a descriptive study on 109 patients who suffer from mental retardation (MR), cerebral palsy (CP), epilepsy (EP), and behavioral disorders (BD), showing also ESA in their encephalic MRI. We studied genomic DNA and transcriptional analysis (cDNA) on EN2 gene (EN2), and in other genes (OG): LIS1, PTAFR, PAFAH1B2, PAFAH1B3, FGF8, PAX2, D17S379, D17S1866, and SMG6 (D17S5), as a routine genetic diagnosis in ESA patients.Results: From 109 patients, fifteen meet the exclusion criteria. From the remaining 94 patients, 12 (12.8%) showed mutations in EN2 (EN2-g), 20 showed mutations in other studied genes (OG-g), and 62 did not showed any mutation (NM-g). All EN2-g patients, suffered from MR, nine EP, seven BD and four CP. The proportions of these phenotypes in EN2-g did not differ from those in the OG-g, but it was significantly higher when comparing EN2-g with NM-g (MR: p = 0.013; EP: p = 0.001; BD: p = 0.0001; CP: p = 0.07, ns). Groups EN2-g and OG-g showed a 100 and a 70% of comorbidity, respectively, being significantly (p = 0.04) greater than NM-group (62.9%).Conclusion: Our series reflects a significant effect of EN2 gene alterations in neurodevelopmental abnormalities associated to ESA. Conversely, although these EN2 related anomalies might represent a predisposition to develop brain diseases, our results did not support direct relationship between EN2 mutations and specific clinical phenotypes.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders involving age-dependent gene dysregulation. Reelin is a glycoprotein that varies its expression throughout lifetime and controls cortical patterning and synaptogenesis. Brain and plasma reelin levels have been reported to be low in adults with autism; as well as in children with autism, but only when compared to control adults. Therefore, reelin expression levels in children with autism are unclear. For this reason, we compared plasma reelin levels in children with autism and children without autism (non-ASD) of similar ages to evaluate reelin expression in ASD during childhood. Plasma samples from 19 non-ASD (8.9 ± 0.8 years) and 40 children with autism (7.5 ± 0.5 years) were analyzed. We found that 50% of the children with autism displayed similar plasma reelin levels to the non-ASD group. However, the remaining 50% expressed more than 30 times more reelin compared to non-ASD levels. We also show that male children with autism displayed significantly higher reelin levels than females. The clinical presentation of this subgroup could not be distinguished from that of children with autism. Epilepsy or attention-deficit/hyperactivity disorder (ADHD) was not associated to reelin levels. We conclude that the high levels of plasma reelin might be an important hallmark in a subset of children with autism, previously unnoticed. As we could not find any correlation between reelin levels and ASD clinical presentations, our results may indicate transient reelin increases in the plasma or the characterization of a group of ASD individuals with a different pathophysiology.
Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.
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