scholarly journals Consequences of NMDA receptor deficiency can be rescued in the adult brain

2017 ◽  
Author(s):  
Catharine A. Mielnik ◽  
Mary A. Binko ◽  
Adam J. Funk ◽  
Emily M. Johansson ◽  
Katheron Intson ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Nmda Receptor ◽  
Neurodevelopmental Disorders ◽  
Gene Editing ◽  
Adult Brain ◽  
Loss Of Function ◽  
Cognitive Behaviors ◽  
Adult Mice ◽  
Activity Dependent ◽  
Nmdar Subunits

AbstractN-methyl-D-aspartate receptors (NMDARs) are required to shape activity-dependent connections in the developing and adult brain. Impaired NMDAR signaling through genetic or environmental insults causes a constellation of neurodevelopmental disorders that manifest as intellectual disability, epilepsy, autism, or schizophrenia. It is not clear whether the developmental impacts of NMDAR dysfunction can be overcome by interventions in adulthood. This question is paramount for neurodevelopmental disorders arising from mutations that occur in the GRIN genes, which encode NMDAR subunits, and the broader set of mutations that disrupt NMDAR function. We developed a mouse model where a congenital loss-of-function allele of Grin1 is restored to wildtype by gene editing with Cre recombinase. Rescue of NMDARs in adult mice yields surprisingly robust improvements in cognitive behaviors, including those that are refractory to treatment with current medications. These results suggest that neurodevelopmental disorders arising from NMDAR deficiency can be effectively treated in adults.

scholarly journals Neuroimaging Findings in Patients with EBF3 Mutations: Report of Two Cases

2021 ◽  
pp. 1-8
Author(s):  
Mar Jiménez de la Peña ◽  
Ana Jiménez de Domingo ◽  
Pilar Tirado ◽  
Beatriz Calleja-Pérez ◽  
Luis A. Alcaraz ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Autosomal Dominant ◽  
De Novo ◽  
Diffusion Tensor ◽  
Loss Of Function ◽  
Normal Range ◽  
Early B Cell Factor ◽  
And Diffusion

Early B cell factor 3 (EBF3) is a transcription factor involved in brain development. Heterozygous, loss-of-function mutations in <i>EBF3</i> have been reported in an autosomal dominant neurodevelopmental syndrome characterized by hypotonia, ataxia, and developmental delay (sometimes described as “HADD”s). We report 2 unrelated cases with novel de novo <i>EBF3</i> mutations: c.455G&#x3e;T (p.Arg152Leu) and c.962dup (p.Tyr321*) to expand the genotype/phenotype correlations of this disorder; clinical, neuropsychological, and MRI studies were used to define the phenotype. IQ was in the normal range and diffusion tensor imaging revealed asymmetric alterations of the longitudinal fasciculus in both cases. Our results demonstrate that <i>EBF3</i> mutations can underlie neurodevelopmental disorders without intellectual disability. Long tract abnormalities have not been previously recognized and suggest that they may be an unrecognized and characteristic feature in this syndrome.

scholarly journals Novel Mutation in LARP7 in Two Iranian Consanguineous Families with Syndromic Intellectual Disability and Facial Dysmorphism

2020 ◽  
Vol 23 (12) ◽  
pp. 842-847
Author(s):  
Goli Kazemi ◽  
Fatemeh Peymani ◽  
Marzieh Mohseni ◽  
Farzane Zare Ashrafi ◽  
Sanaz Arzhangi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Novel Mutation ◽  
Facial Dysmorphism ◽  
Loss Of Function ◽  
Disease Mechanism ◽  
Acceptor Splice Site ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Iranian Patients

Background: Recently, we have reported mutations in LARP7 gene, leading to neurodevelopmental disorders (NDDs), the most frequent cause of disability in children with a broad phenotype spectrum and diverse genetic landscape. Methods: Here, we present two Iranian patients from consanguineous families with syndromic intellectual disability, facial dysmorphism, and short stature. Results: Whole-exome sequencing (WES) revealed a novel homozygous stop-gain (c.C925T, p.R309X) variant and a previously known homozygous acceptor splice-site (c.1669-1_1671del) variant in LARP7 gene, indicating the diagnosis of Alazami syndrome. Conclusion: These identified variants in patients with Alazami syndrome were consistent with previously reported loss of function variants in LARP7 and provide further evidence that loss of function of LARP7 is the disease mechanism.

scholarly journals Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With “Developmental and Epileptic Encephalopathy”

2020 ◽  
Vol 11 ◽  
Author(s):  
Emanuela Leonardi ◽  
Elisa Bettella ◽  
Maria Federica Pelizza ◽  
Maria Cristina Aspromonte ◽  
Roberta Polli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Hot Spot ◽  
Genetic Diagnosis ◽  
Epileptic Encephalopathy ◽  
Gene Panel ◽  
Loss Of Function ◽  
Speech Impairment ◽  
Mild Intellectual Disability

SETBP1 mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of SETBP1, two novel de novo truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified SETBP1 variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C&gt;T (p.Arg589*) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19*) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G&gt;A (p.Glu858Lys) variant, which is absent from the control population, reported as de novo in a subject with ASD, and located close to the SETBP1 hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of SETBP1 in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to “developmental and epileptic encephalopathy” (DEE).

scholarly journals Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

2021 ◽  
Author(s):  
Meena Balasubramanian ◽  
Alexander J. M. Dingemans ◽  
Shadi Albaba ◽  
Ruth Richardson ◽  
Thabo M. Yates ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protein Function ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Mild Intellectual Disability ◽  
Related Disorder ◽  
Feeding Difficulties ◽  
Facial Phenotype ◽  
Novel Variants ◽  
Common Behaviour

AbstractWitteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

scholarly journals Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability

Small GTPases ◽  
2021 ◽  
pp. 1-8
Author(s):  
Viviane Tran ◽  
Marie-Anne Goyette ◽  
Mónica Martínez-García ◽  
Ana Jiménez de Domingo ◽  
Daniel Martín Fernández-Mayoralas ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Loss Of Function

scholarly journals Immunity and mental illness: findings from a Danish population-based immunogenetic study of seven psychiatric and neurodevelopmental disorders

2019 ◽  
Vol 27 (9) ◽  
pp. 1445-1455 ◽  
Author(s):  
Ron Nudel ◽  
Michael E. Benros ◽  
Morten Dybdahl Krebs ◽  
Rosa Lundbye Allesøe ◽  
Camilla Koldbæk Lemvigh ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protective Effect ◽  
Neurodevelopmental Disorders ◽  
Association Studies ◽  
Human Leukocyte ◽  
Population Based ◽  
Autism Spectrum ◽  
Small Samples ◽  
Hla Association ◽  
Hla Genes

AbstractHuman leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants’ HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

scholarly journals Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph J. Rossi ◽  
Jill A. Rosenfeld ◽  
Katie M. Chan ◽  
Haley Streff ◽  
Victoria Nankivell ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Neurodevelopmental Disorder ◽  
Complete Loss ◽  
Loss Of Function ◽  
Targeted Disruption ◽  
Clinical Exome Sequencing ◽  
Partner Protein ◽  
The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

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