Figure 3 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Brain hypoplasia in Rereom/eyes3 embryos and mice. A) The brains of Rereom/eyes3 embryos and mice appeared smaller than those of their wild-type litter mates at E17.5, E18.5 and P0 but no difference in overall morphology was observed between genotypes. B) Coronal brain sections from wild-type and Rereom/eyes3 embryos at E18.5 were also comparable except for size. Representative examples of these sections are shown. Scale bar indicates 500 µm. C–D) The surface areas of the cerebral hemispheres (C) and cerebellum (D) were significantly reduced in Rereom/eyes3 embryos and mice in comparison with those of wild-type embryos and mice between E17.5 and P0 (n≥5; * = p<0.03). E) Whole brain weights were also significantly decreased in Rereom/eyes3 embryos and mice in comparison with those of wild-type embryos and mice between E17.5 and P0 (n≥5; * = p<0.01).
Source publication
Individuals with terminal and interstitial deletions of chromosome 1p36 have a spectrum of defects that includes eye anomalies, postnatal growth deficiency, structural brain anomalies, seizures, cognitive impairment, delayed motor development, behavior problems, hearing loss, cardiovascular malformations, cardiomyopathy, and renal anomalies. The pr...
Citations
... RERE (MIM*605226) is situated in the proximal region of chromosome 1p36. 10 RERE serves as a nuclear receptor co-regulator in retinoic acid signaling across multiple tissues during embryonic development. 11,12 Previous studies have reported various clinical phenotypes associated with RERE variants, including hypotonia, behavioral issues, structural central nervous system (CNS) abnormalities, seizures, ophthalmologic abnormalities, congenital heart defects, genitourinary abnormalities, 13 and sensorineural hearing loss. ...
Autism spectrum disorder (ASD) is a highly variable neurodevelopmental disorder that typically manifests childhood, characterized by a triad of symptoms: impaired social interaction, communication difficulties, and restricted interests with repetitive behaviors. De novo variants in related genes can cause ASD. We present the case of a 6‐year‐old Chinese boy with autistic behavior, including language communication impairments, intellectual disabilities, stunted development, and irritability in social interactions. Using Sanger sequencing, we confirmed a pathogenic in the RERE gene (NM_012102.4) (c.3732delC, p.Tyr1245Thrfs*12; EX21; Het). Subsequently, we generated an RERE point mutation cell line (ReMut) using CRISPR/Cas9 Targeted Genome Editing. Immunofluorescence was conducted to determine the location of the mutant RERE. RNA‐sequencing and mass spectrometry analyses were performed to elucidate the ASD‐related genes and signaling pathways disrupted by this variant in RERE. We identified 3790 differentially expressed genes and 684 differentially expressed proteins. The SHH signaling pathway was found to be downregulated, and the Hippo pathway was upregulated in ReMut. Genes implicated in autism, such as CNTNAP2, STX1A, FARP2, and GPC1, were significantly downregulated. Simultaneously, we noted alterations in HDAC1 and HDAC2, which are members of the WHHERE complex, suggesting their role in the pathogenesis of this patient. In conclusion, we report a de novo variant in RERE associated with autistic behavior. The finding that ASD is associated with RERE variants underscore the role of genetic factors in ASD and provides insights regarding the mechanisms underlying RERE variants in disease onset.
... RERE (arginine-glutamic acid dipeptide repeats) is another brain-enriched gene that is significantly deleted in autistic patients [26]. According to studies on zebrafish and mouse models, mutation and haploinsufficiency of RERE leads to NDDs, ID, DD and kidney problems [26,29,30,[33][34][35]. These data showed that RERE mutation carriers and autistic individuals had some common phenotypes, indicating this gene is a plausible strong contributor to ASD. ...
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder (NDD) that is caused by genetic, epigenetic, and environmental factors. Recent advances in genomic analysis have uncovered numerous candidate genes with common and/or rare mutations that increase susceptibility to ASD. In addition, there is increasing evidence that copy number variations (CNVs), single nucleotide polymorphisms (SNPs), and unusual de novo variants negatively affect neurodevelopment pathways in various ways. The overall rate of copy number variants found in patients with autism is 10%-20%, of which 3%-7% can be detected cytogenetically. Although the role of submicroscopic CNVs in ASD has been studied recently, their association with genomic loci and genes has not been properly studied. In this review, we focus on 47 ASD-associated CNV regions and their related genes. Here, we identify 1,632 protein-coding genes and long non-coding RNAs (lncRNAs) within these regions. Among them, 552 are significantly expressed in the brain. Using a list of ASD-associated genes from SFARI, we detect 17 regions containing at least one known ASD-associated protein-coding genes. Of the remaining 30 regions, we identify 24 regions containing at least one protein-coding genes with brain-enriched expression and nervous system phenotype in mouse mutant and one lncRNAs with both brain-enriched expression and upregulation in iPSC to neuron differentiation. Our analyses highlight the diversity of genetic lesions of CNV regions that contribute to ASD and provide new genetic evidence that lncRNA genes may contribute to etiology of ASD. In addition, the discovered CNVs will be a valuable resource for diagnostic facilities, therapeutic strategies, and research in terms of variation priority.
... It has been suggested that another gene: RERE (Arginineglutamic acid dipeptide repeats) may be responsible for microcephaly in 1p36DS. Indeed, Kim et al. observed a reduced brain size in Rere mutant mice (Kim et al., 2013). However, only two Group B deletions encompassed RERE. ...
Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second‐largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow‐up of patients.
... ENU mutagenesis is a particularly valuable methodology to recover an allelic series of point mutations for any gene enabling a more acute analysis of gene function [61][62][63][64][65][66][67][68]. To date, 441 genes for which mutations result in rare human skeletal disorders are listed by the 2019 International Skeletal Dysplasia Society, from which 260 genes were examined for skeletal phenotypes using mutant mice and 37 phenotypes were successfully identified by ENU mouse mutagenesis [69]. ...
PhexL222P mouse is a new ENU mouse model for XLH disease due to Leu to Pro amino acid modification at position 222. PhexL222P mouse is characterized by growth retardation, hypophosphatemia, hypocalcemia, reduced body bone length, and increased epiphyseal growth plate thickness and femur diameter despite the increase in PHEXL222P expression. Actually, PhexL222P mice show an increase in Fgf23, Dmp1, and Mepe and Slc34a1 (Na-Pi IIa cotransporter) mRNA expression similar to those observed in Hyp mice. Femoral osteocalcin and sclerostin and Slc34a1 do not show any significant variation in PhexL222P mice. Molecular dynamics simulations support the experimental data. P222 might locally break the E217-Q224 β-sheet, which in turn might disrupt inter-β-sheet interactions. We can thus expect local protein misfolding, which might be responsible for the experimentally observed PHEXL222P loss of function. This model could be a valuable addition to the existing XLH model for further comprehension of the disease occurrence and testing of new therapies.
... 3 In contrast, mice carrying an om null allele and an Rere hypomorphic allele (eyes3) can survive into adulthood on a mixed B6/SV129 background. 5 Rere om/eyes3 embryos and mice on varying genetic backgrounds have variety of abnormal phenotypes including postnatal growth retardation, brain defects, eye defects, hearing loss, congenital heart defects, cardiac fibriosis, and renal agenesis. [5][6][7][8] Similar phenotypes have now been documented in humans bearing heterozygous, loss-of-function and missense variants in RERE. ...
... 5 Rere om/eyes3 embryos and mice on varying genetic backgrounds have variety of abnormal phenotypes including postnatal growth retardation, brain defects, eye defects, hearing loss, congenital heart defects, cardiac fibriosis, and renal agenesis. [5][6][7][8] Similar phenotypes have now been documented in humans bearing heterozygous, loss-of-function and missense variants in RERE. 6,9 The most common phenotypes associated with decreased F I G U R E 1 The expression pattern of RERE in the developing mouse retina. ...
... 6,9 Similarly, RERE-deficient mice have been described to have microphthalmia, coloboma, and optic nerve hypoplasia. 5,6 Zebrafish bearing a mutant allele of rerea, the zebrafish homologue of RERE, also have microphthalmia. 10,11 These data suggest that RERE plays an important role in vertebrate eye development. ...
Background
The arginine‐glutamic acid dipeptide repeats gene (RERE) encodes a nuclear receptor coregulator that modulates gene expression through its interaction with transcriptional machinery. In humans, RERE deficiency causes neurodevelopmental disorder with or without structural defects of the brain, eye, heart, and kidney (NEDBEH). Ophthalmological defects are seen in approximately one third of individuals with NEDBEH and in RERE‐deficient mice which can serve as a useful animal model.
Results
In mice, RERE is expressed in a subset of retinal ganglion cells (RGC), the lens epithelium, and the ciliary body during the embryonic period. RERE expression expands into the outer nuclear layer and the inner nuclear layer during the postnatal period. RERE‐deficient mice have retinal and optic nerve atrophy. We show that RERE deficiency causes progressive loss of retinal cells and apoptosis of retinal cells in the ganglion cell layer as early as E17.5. The number of RGCs is also reduced in RERE‐deficient embryos and mice.
Conclusions
We conclude that RERE is required to control the apoptosis of retinal cells in the developing retina, and that RERE deficiency results in the retina atrophy through degeneration of the retinal cells and optic nerve atrophy through the loss of RGCs.
... We have previously shown that on a mixed B6/129S6 background, mice bearing both a null allele (om) and a hypomorphic allele (eyes3) of Rere have a spectrum of malformations that is similar to that seen in humans with proximal 1p36 deletions and NEDBEH (3,9). These phenotypes include postnatal growth deficiency, brain hypoplasia, structural brain anomalies, microphthalmia, hearing loss, congenital heart defects and renal anomalies. ...
... Orofacial clefts were not documented in Rere om/eyes3 mice in this mixed background. However, some defects, particularly congenital heart defects, are only seen on a pure B6 background, which is also associated with an increased level of embryonic/perinatal mortality (9). ...
... Wild-type C57BL/6 embryos were used to define the expression pattern of RERE. The generation of the Rere om, null and eyes3 alleles was described previously (5,9). Experiments involving mice bearing these alleles were conducted on a C57BL/6 background. ...
Deletions of chromosome 1p36 are the most common telomeric deletions in humans and are associated with an increased risk of orofacial clefting. Deletion/phenotype mapping, combined with data from human and mouse studies, suggests the existence of multiple 1p36 genes associated with orofacial clefting including SKI, PRDM16, PAX7, and GRHL3. The arginine-glutamic acid dipeptide (RE) repeats gene (RERE) is located in the proximal critical region for 1p36 deletion syndrome and encodes a nuclear receptor co-regulator. Pathogenic RERE variants have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Cleft lip has previously been described in one individual with NEDBEH. Here we report the first individual with NEDBEH to have a cleft palate. We confirm that RERE is broadly expressed in the palate during mouse embryonic development, and we demonstrate that the majority of RERE-deficient mouse embryos on C57BL/6 background have cleft palate. We go on to show that ablation of Rere in cranial neural crest cells, mediated by a Wnt1-Cre, leads to delayed elevation of the palatal shelves and cleft palate, and that proliferation of mesenchymal cells in the palatal shelves is significantly reduced in Rereflox/flox; Wnt1-Cre embryos. We conclude that loss of RERE function contributes to the development of orofacial clefts in individuals with proximal 1p36 deletions and NEDBEH, and that RERE expression in cranial neural crest cells and their derivatives is required for normal palatal development.
... This protein was shown to be a nuclear receptor coregulator interacting with NR2F2 and NR2E1 [32,33] and to interact with histone deacetylases in the mouse embryo [31,34], but its function is not completely elucidated [34]. Different mouse models with null or hypomorphic RERE alleles have been produced [35][36][37]. These models revealed that a deficiency of RERE leads to a wide range of developmental defects including the brain, heart, and kidney. ...
While chromosome 1p36 deletion syndrome is one of the most common terminal subtelomeric microdeletion syndrome, 1p36 microduplications are rare events. Polymicrogyria (PMG) is a brain malformation phenotype frequently present in patients with 1p36 monosomy. The gene whose haploinsufficiency could cause this phenotype remains to be identified. We used high-resolution arrayCGH in patients with various forms of PMG in order to identify chromosomal variants associated to the malformation and characterized the genes included in these regions in vitro and in vivo. We identified the smallest case of 1p36 duplication reported to date in a patient presenting intellectual disability, microcephaly, epilepsy and perisylvian polymicrogyria (PMG). The duplicated segment is intrachromosomal, duplicated in mirror and contains two genes: ENO1 and RERE, both disrupted by the rearrangement. Gene expression analysis performed using the patient cells revealed a reduced expression, mimicking haploinsufficiency. We performed in situ hybridization to describe the developmental expression profile of the two genes in mouse development. In addition, we used in utero electroporation of shRNAs to show that Eno1 inactivation in the rat causes a brain development defect. These experiments allowed us to define the enolase 1 (ENO1) gene as the most likely candidate to contribute to the brain malformation phenotype of the studied patient and consequently a candidate to contribute to the malformations of the cerebral cortex observed in patients with 1p36 monosomy.
... reduced proliferation of cardiomyocytes and ventral septal defect, and is implicated in neurogenesis [89]. RERE Apoptosis 26.6 39.8 RERE has been implicated in many organs [90] and is highly expressed in the brain and heart. RERE has been implicated in many roles including cerebellar development [91], and heart tube looping [92]. ...
Copy number variant (CNV) syndromes are often associated with both neurocognitive deficits (NCDs) and congenital heart defects (CHDs). Children and adults with cardiac developmental defects likely to have NCDs leading to increased risk of hospitalisation and reduce independence. To date, the association between these two phenotypes have not been explored in relation to CNV syndromes. In order to address this question, we systematically reviewed the prevalence of CHDs in a range of CNV syndromes associated with NCDs. A meta-analysis showed a relationship with the size of CNV and its association with both NCDs and CHDs, and also inheritance pattern. To our knowledge, this is the first review to establish association between NCD and CHDs in CNV patients, specifically in relation to the severity of NCD. Importantly, we found specific types of CHDs were associated with severe neurocognitive deficits. Finally, we discuss the implications of these results for patients in the clinical setting which warrants further exploration of this association in order to lead improvement in the quality of patient's life.
... Thus, RERE may play a pivotal role in normal brain development. 31,32 In addition, a recent report indicated that RERE and its Drosophila homolog were associated with histone methyltransferases in the regulation of gene expression. 33 Gene-environment interactions play an essential role in MDD pathogenesis, which is a polygenic and heterogeneous disease. ...
Objective
Recently, a genome-wide association study successfully identified genetic variants associated with major depressive disorder (MDD). The study identified 17 independent single-nucleotide polymorphisms (SNPs) significantly associated with diagnosis of MDD. These SNPs were predicted to be enriched in genes that are expressed in the central nervous system and function in transcriptional regulation associated with neurodevelopment. The study aimed to investigate associations between 17 SNPs and brain morphometry using magnetic resonance imaging (MRI) in drug-naïve patients with MDD and healthy controls (HCs).
Methods
Forty-seven patients with MDD and 42 HCs were included. All participants underwent T1-weighted structural MRI and genotyping. The genotype–diagnosis interactions associated with regional cortical thicknesses were evaluated using voxel-based morphometry for the 17 SNPs.
Results
Regarding rs301806, an SNP in the RERE genomic regions, we found a significant difference in a genotype effect in the right-lateral orbitofrontal and postcentral lobes between diagnosis groups. After testing every possible diagnostic comparison, the genotype–diagnosis interaction in these areas revealed that the cortical thickness reductions in the MDD group relative to those in the HC group were significantly larger in T/T individuals than in C-carrier ones. For the other SNPs, no brain area was noted where a genotype effect significantly differed between the two groups.
Conclusions
We found that a RERE gene SNP was associated with cortical thickness reductions in the right-lateral orbitofrontal and postcentral lobes in drug-naïve patients with MDD. The effects of RERE gene polymorphism and gene–environment interactions may exist in brain structures of patients with MDD.
... Thus, RERE appears to be required for normal brain development. 23,24 Furthermore, a recent report indicates that RERE and its Drosophila homolog associate with histone methyltransferases to regulate gene expression. 25 MDD is a polygenic and multifactorial disease, and gene-environment interactions play a pivotal role in its pathophysiology. ...
Background
A genome-wide association study using megadata identified 17 single-nucleotide polymorphisms (SNPs) in candidate genes for major depressive disorder (MDD). These MDD susceptibility polymorphisms may affect white matter (WM) integrity. This study aimed to investigate the relationship between WM alterations and 17 SNPs in candidate genes for MDD in the first depressive episode of drug-naive MDD patients using a tract-based spatial statistics (TBSS) method.
Methods
Thirty-five drug-naive MDD patients with a first depressive episode and 47 age-and sex-matched healthy subjects underwent diffusion tensor imaging scans and genotyping. The genotype–diagnosis interactions related to WM integrity were evaluated using TBSS for the 17 SNPs.
Results
For the anterior thalamic radiation, cingulum, corticospinal tract, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, forceps major, and forceps minor, the genotype effect significantly differed between diagnosis groups (P<0.05, family-wise error corrected) in only one SNP, rs301806, in the arginine–glutamic acid dipeptide (RE) repeats (RERE) gene.
Conclusion
The RERE polymorphism was associated with WM alterations in first-episode and drug-naive MDD patients, which may be at least partially related to the manifestation of MDD. Future studies are needed to explore the gene–environment interactions with regard to individual WM integrity.
