Abstract
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.
Highlights
The engrailed homeobox protein plays an important role during development in the invertebrate segmentation, where it is required for the formation of posterior compartments in larva segments
From the 109 included patients, 15 patients who were diagnosed of encephalic structural anomalies (ESA) and the other inclusion criteria, but the clinical history reported suffering from some syndromic condition with known gene mutation or whose symptoms could be related to inflammatory or infectious diseases were removed from the analyzed series
EN2-g patients showed EN2 genetic deletions in genomic DNA and/or cDNA (Table 5), that did not correspond to reported alteration in EN2 expression splicing, single-nucleotide variants or polymorphisms
Summary
The engrailed homeobox protein (en) plays an important role during development in the invertebrate segmentation, where it is required for the formation of posterior compartments in larva segments. The EN protein has been involved the regionalization of the mid-hindbrain segment of the neural tube. It is a reference transcription factor coding positional information in the cerebellum morphogenesis and retinotectal synaptogenesis (Martinez et al, 1991; Friedman and O’Leary, 1996; Cheng et al, 2010). The En2 expression in the mid-hindbrain segment is induced by Fgf signal from the isthmic organizer (Crossley et al, 1996; Martinez et al, 1999) and it is required to specify mesencephalic and cerebellar development, including serotoninergic and dopaminergic neurons in the raphe nuclei, substantia nigra, and ventral tegmental area (Millen et al, 1994; Wurst et al, 1994; Simon et al, 2005; Sonnier et al, 2007). The expression gradient of En2 in the tectum regulates the normal establishment of the retinotopic pattern of retinal innervation (Araki and Nakamura, 1999; Nakamura and Sugiyama, 2004)
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