Report of a novel missense mutation in the MECP2 gene in a middle-aged man with intellectual disability syndrome.
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ABSTRACT:
SUBMITTER: Arvio M
PROVIDER: S-EPMC8380086 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWe recently described a novel autosomal recessive neurodevelopmental disorder with intellectual disability in four patients from two related Hutterite families. Identity-by-descent mapping localized the gene to a 5.1 Mb region at chromosome 16p13.3 containing more than 170 known or predicted genes. The objective of this study was to identify the causative gene for this rare disorder.Methods and resultsCandidate gene sequencing followed by exome sequencing identified a homozygous missense mutation p.Gly46Arg, in THOC6. No other potentially causative coding variants were present within the critical region on chromosome 16. THOC6 is a member of the THO/TREX complex which is involved in coordinating mRNA processing with mRNA export from the nucleus. In situ hybridization showed that thoc6 is highly expressed in the midbrain and eyes. Cellular localization studies demonstrated that wild-type THOC6 is present within the nucleus as is the case for other THO complex proteins. However, mutant THOC6 was predominantly localized to the cytoplasm, suggesting that the mutant protein is unable to carry out its normal function. siRNA knockdown of THOC6 revealed increased apoptosis in cultured cells.ConclusionOur findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.
| S-EPMC3644499 | biostudies-literature
Project description:Methyl-CpG-binding protein 2 (MeCP2) is a nuclear protein highly expressed in neurons that is involved in transcriptional modulation and chromatin remodeling. Mutations in MECP2 in females are associated with Rett syndrome, a neurological disorder characterized by a normal neonatal period, followed by the arrest of development and regression of acquired skills. Although it was initially thought that MECP2 pathogenic mutations in males were not compatible with life, starting from 1999 about 60 male patients have been identified and their phenotype varies from severe neonatal encephalopathy to mild intellectual disability. Targeted next-generation sequencing of a panel of intellectual disability related genes was performed on two unrelated male patients, and two missense variants in MECP2 were identified (p.Gly185Val and p.Arg167Trp). These variants lie outside the canonical methyl-CpG-binding domain and transcription repression domain domains, where the pathogenicity of missense variants is more difficult to establish. In both families, variants were found in all affected siblings and were inherited from the asymptomatic mother, showing skewed X-chromosome inactivation. We report here the first missense variant located in AT-hook domain 1 and we underline the importance of MECP2 substitutions outside the canonical MeCP2 domains in X-linked intellectual disability.
| S-EPMC4770571 | biostudies-literature
Project description:The small GTPase Rac1 promotes actin polymerization and plays a critical and increasingly appreciated role in the development and plasticity of glutamatergic synapses. Growing evidence suggests that disruption of the Rac1 signaling pathway at glutamatergic synapses contributes to Autism Spectrum Disorder/intellectual disability (ASD/ID)-related behaviors seen in animal models of ASD/ID. Rac1 has also been proposed as a strong candidate of convergence for many factors implicated in the development of ASD/ID. However, the effects of ASD/ID-related mutations in Rac1 itself have not been explored in neurons. Here, we investigate a recently reported de novo missense mutation in Rac1 found in an individual with severe ID. Our modeling predicts that this mutation will strongly inhibit Rac1 activation by occluding Rac1's GTP binding pocket. Indeed, we find that this de novo mutation prevents Rac1 function and results in a selective reduction in synaptic AMPA receptor function. Furthermore, this mutation prevents the induction of long-term potentiation (LTP), the cellular mechanism underlying learning and memory formation. Together, our findings strongly suggest that this mutation contributes to the development of ID in this individual. This research demonstrates the importance of Rac1 in synaptic function and plasticity and contributes to a growing body of evidence pointing to dysregulation of actin polymerization at glutamatergic synapses as a contributing factor to ASD/ID.
| S-EPMC6049044 | biostudies-literature
Project description:Recently, exome sequencing has extended our knowledge of genetic causes of developmental delay through identification of de novo, germline mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) in 13 patients with neurodevelopmental disability and a wide range of additional symptoms and signs including hypotonia in 11 and seizures in 10 of the patients. Limb/arm dystonia was found in 2 patients.(1).
| S-EPMC5022844 | biostudies-literature
Project description:Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.
| S-EPMC4313821 | biostudies-other
Project description:Disease gene discovery in neurodevelopmental disorders, including X-linked intellectual disability (XLID) has recently been accelerated by next-generation DNA sequencing approaches. To date, more than 100 human X chromosome genes involved in neuronal signaling pathways and networks implicated in cognitive function have been identified. Despite these advances, the mutations underlying disease in a large number of XLID families remained unresolved. We report the resolution of MRX78, a large family with six affected males and seven affected females, showing X-linked inheritance. Although a previous linkage study had mapped the locus to the short arm of chromosome X (Xp11.4-p11.23), this region contained too many candidate genes to be analyzed using conventional approaches. However, our X-chromosome exome resequencing, bioinformatics analysis and inheritance testing revealed a missense mutation (c.C2366T, p.A789V) in IQSEC2, encoding a neuronal GDP-GTP exchange factor for Arf family GTPases (ArfGEF) previously implicated in XLID. Molecular modeling of IQSEC2 revealed that the A789V substitution results in the insertion of a larger side-chain into a hydrophobic pocket in the catalytic Sec7 domain of IQSEC2. The A789V change is predicted to result in numerous clashes with adjacent amino acids and disruption of local folding of the Sec7 domain. Consistent with this finding, functional assays revealed that recombinant IQSEC2(A789V) was not able to catalyze GDP-GTP exchange on Arf6 as efficiently as wild-type IQSEC2. Taken together, these results strongly suggest that the A789V mutation in IQSEC2 is the underlying cause of XLID in the MRX78 family.
| S-EPMC4707274 | biostudies-literature
Project description:Fine scale genomic regulation is critical for maintaining genomic integrity and is often disrupted in neurodevelopmental disorders. An intriguing new study reveals the intricate biochemical complexity of de novo post-translational modifications of MeCP2, including activity-dependent protein-protein interactions that 'bridge' the nuclear receptor co-repressor (NCoR) complex to chromatin and lead to alterations in gene expression that characterize Rett syndrome.
| S-EPMC3817541 | biostudies-other
Project description:BACKGROUND:Intellectual disability (ID) constitutes the most common group of neurodevelopmental disorders. Exome sequencing has enabled the discovery of genetic mutations responsible for a wide range of ID disorders. CASE PRESENTATION:In this study, we reported on two male siblings, aged 4 and 2?years, with motor and mental developmental delays and mild dysmorphic facial features. To identify the genetic causes of these symptoms, we employed trio-whole exome sequencing for the proband. We found a novel hemizygous missense variant in the PAK3 gene (c.1112G?>?A, p.Cys371Tyr), which encodes the p21-activated kinase 3, in the proband, which inherited from mother. The younger brother also has the hemizygous variant, which was confirmed by Sanger sequencing. The variant is located in the kinase domain and was regarded as a likely pathogenic variant in this family. CONCLUSION:We diagnosed two male siblings with developmental delays as having a PAK3 likely pathogenic variant. This finding expands the list of PAK3 gene mutations associated with neurodevelopmental disorders and provides further details on its clinical features.
| S-EPMC7017536 | biostudies-literature
Project description:Transcription factor 4 (TCF4) is a basic helix-loop-helix transcription factor essential for neurocognitive development. The aberrations in TCF4 are associated with neurodevelopmental disorders including schizophrenia, intellectual disability, and Pitt-Hopkins syndrome, an autism-spectrum disorder characterized by developmental delay. Several disease-associated missense mutations in TCF4 have been shown to interfere with TCF4 function, but for many mutations, the impact remains undefined. Here, we tested the effects of 12 functionally uncharacterized disease-associated missense mutations and variations in TCF4 using transient expression in mammalian cells, confocal imaging, in vitro DNA-binding assays, and reporter assays. We show that Pitt-Hopkins syndrome-associated missense mutations within the basic helix-loop-helix domain of TCF4 and a Rett-like syndrome-associated mutation in a transcription activation domain result in altered DNA-binding and transcriptional activity of the protein. Some of the missense variations found in schizophrenia patients slightly increase TCF4 transcriptional activity, whereas no effects were detected for missense mutations linked to mild intellectual disability. We in addition find that the outcomes of several disease-related mutations are affected by cell type, TCF4 isoform, and dimerization partner, suggesting that the effects of TCF4 mutations are context-dependent. Together with previous work, this study provides a basis for the interpretation of the functional consequences of TCF4 missense variants.
| S-EPMC8648840 | biostudies-literature
Project description:Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor.This study presents, clinically and molecularly, an Emirati patient with de novo frameshift mutation in CTCF. This novel mutation was uncovered using whole exome sequencing and was confirmed by Sanger sequencing in the trio. In silico analysis, using SIFT Indel, indicates that this frameshift; p.Lys206Profs*13 is functionally damaging with the likely involvement of nonsense-mediated mRNA decay.Upon comparing the clinical picture of the herewith-reported individual with previously reported cases of MRD21, there seems to be many common symptoms, and few new ones that were not observed before. This helps to further define this rare condition and its molecular underpinnings.
| S-EPMC5472882 | biostudies-literature