Mutations in GEMIN5 cause a neurodevelopmental ataxia syndrome by a loss-of-1function mechanism
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ABSTRACT:
PROVIDER: PRJNA713291 | ENA |
REPOSITORIES: ENA
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Project description:GEMIN5 is a critical component of snRNP assembly complex. Patients carrying novel autosomal recessive variants in the GEMIN5 gene showed symptoms of developmental delay, central hypotonia, and cerebellar ataxia which are distinct than classical spinal muscular atrophy. We performed RNA-seq analysis in iPSC-derived differentiated neurons with biallelic GEMIN5-H913R mutation to identify global alterations in various genes and pathways mediated by GEMIN5 mutations in patients.
2021-03-11 | GSE168622 | GEO
Project description:Integrator (INT) is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. INT has at least 14 subunits, but INT germline mutations causing human disease have not been reported. We identified mutations in the Integrator Complex Subunit 8 gene (INTS8) causing a rare neurodevelopmental syndrome. In patient cells we identified significant disturbance of gene expression and RNA processing. Also, we show that injection of ints8 oligonucleotide morpholinos into zebrafish embryos leads to prominent underdevelopment of the head demonstrating the evolutionary conserved requirement of INTS8 in brain development. RNA sequencing was carried out using RNA samples from fibroblasts from two individuals with germline bi-allelic INTS8 mutations and from two healthy individuals
2017-05-17 | E-GEOD-76878 | biostudies-arrayexpress
Project description:Integrator (INT) is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. INT has at least 14 subunits, but INT germline mutations causing human disease have not been reported. We identified mutations in the Integrator Complex Subunit 8 gene (INTS8) causing a rare neurodevelopmental syndrome. In patient cells we identified significant disturbance of gene expression and RNA processing. Also, we show that injection of ints8 oligonucleotide morpholinos into zebrafish embryos leads to prominent underdevelopment of the head demonstrating the evolutionary conserved requirement of INTS8 in brain development.
2017-05-17 | GSE76878 | GEO
Project description:Mutations in NCAPG2 cause a severe neurodevelopmental syndrome that expands the phenotypic spectrum of condensinopathies
| PRJNA506958 | ENA
Project description:From a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism carrying a deleterious variant in the EBF3 (Early B-cell Factor 3) gene detected by whole-exome sequencing. Five missense, two nonsense, one 9-bp duplication, and one splice-site variant in EBF3 were found; the mutation occurred de novo in eight individuals, and the missense variant c.625C>T [p.(Arg209Trp)] was inherited by two affected siblings from their healthy mother who is a mosaic. EBF3 belongs to the early B-cell factor family (also known as Olf, COE, or O/E) and encodes a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicts damaging effects of the five amino acid substitutions on DNA-binding of EBF3. Transient expression of EBF3 mutant proteins in HEK 293T cells revealed mislocalization of all but one mutant in the cytoplasm in addition to nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the CDKN1A reporter gene, and EBF3 mutant proteins were less tightly associated with chromatin as demonstrated by in situ subcellular fractionation experiments. Finally, RNA-seq and ChIP-seq experiments demonstrate that EBF3 acts as a transcriptional regulator and EBF3 mutant protein had reduced genome-wide DNA binding and gene regulatory activity. Our findings demonstrate that variants that disrupt EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay, and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders.
2016-11-30 | GSE90682 | GEO
Project description:The use of whole exome/genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here we report two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects; failure to thrive; ocular abnormalities; and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin bridge formation and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically-relevant phenotypes, such as microcephaly and renal anomalies with concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR/Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous deletion of NPHP1, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy and highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.
2018-11-27 | GSE122932 | GEO
Project description:Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation.
| S-EPMC5223060 | biostudies-literature
Project description:During endosomal trafficking, the ubiquitin-status of membrane-bound protein cargo determines whether it is recycling to the surface or trafficked through intermediate multivesicular bodies (MVBs) for lysosomal degradation. Neurons, particularly their synapses, are extremely sensitive to perturbations in endolysosomal transport. We describe a lethal severe neurodevelopmental disorder (characterised by limb hypertonia, central hypotonia, progressive spasticity, seizures, secondary microcephaly and no developmental progress) in seven infants from three kindreds with a homozygous G23V PLAA mutation. PLAA is an ubiquitiously expressed and highly conserved ubiquitin-binding adaptor protein implicated in proteostasis. A mouse Plaa knockout was embyonically lethal but using CRISPR gene editing we recreated an allelic G23V series of Plaa mouse mutants leading to early onset neural dysfunction and death. Unlike in yeast, mammalian Plaa mutant cells do not globally affect free ubiquitin homeostasis but show defects in the capture and processing of ubiquitinated-membrane cargo for concentration into functional MVBs disrupting basal macroautophagy.
2018-07-11 | PXD003140 | Pride
Project description:Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.
| S-EPMC5384036 | biostudies-literature
Project description:Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels.
| S-EPMC6174320 | biostudies-literature