Function Of Domain Research Articles

The F-BAR Domain of Rga7 Relies on a Cooperative Mechanism of Membrane Binding with a Partner Protein during Fission Yeast Cytokinesis

SUMMARYF-BAR proteins bind the plasma membrane (PM) to scaffold and organize the actin cytoskeleton. To understand how F-BAR proteins achieve their PM association, we studied the localization of a Schizosaccharomyces pombe F-BAR protein Rga7, which requires the coiled-coil protein Rng10 for targeting to the division site during cytokinesis. We find that the Rga7 F-BAR domain directly binds a motif in Rng10 simultaneously with the PM, and that an adjacent Rng10 motif independently binds the PM. Together, these multivalent interactions significantly enhance Rga7 F-BAR avidity for membranes at physiological protein concentrations, ensuring the division site localization of Rga7. Moreover, the requirement for the F-BAR domain in Rga7 localization and function in cytokinesis is bypassed by tethering an Rga7 construct lacking its F-BAR to Rng10, indicating that at least some F-BAR domains are necessary but not sufficient for PM targeting and are stably localized to specific cortical positions through adaptor proteins.

The tubulin mutation database: A resource for the cytoskeleton community.

Over the last 40 years, the phenotypic consequences of point mutations to tubulin genes have been described in a wide variety of eukaryotes. A publicly available web-based catalog of all published point mutations to tubulin was assembled. Each entry records a specific substitution to a discrete tubulin, the species where the mutation was described, the associated phenotype, and provides hyperlinks to the parental amino acid sequence and citation(s) for the original research. The data is represented in individual tables for the universal tubulin families (α-, β-, and γ-tubulins) with the smaller datasets for point mutations to δ-, ε-, and ζ-tubulins individually appended to the γ-tubulin mutation table. Because tubulins are highly conserved proteins, the benefit of organizing the database tables in order of amino acid position is that comparison between equivalent residues in different isotypes or species is straightforward. For example, it was shown that seven substitutions which are associated with human brain malformations known as tubulinopathies were previously identified in other contexts that suggest that they influence microtubule stability. It was anticipated that this resource will simplify evaluation of the role of specific amino acids or domains in microtubule function.

Morpho-Structural Mapping Constraints from Geophysical and Test Pit Investigations: Case Study of the Bomkoul Locality in Douala Sedimentary Basin, Cameroon, Central Africa

A survey using the electrical resistivity and test pit methods is carried out in the Douala subbasin in order to investigate the sub-surface layering and evaluate the thickness of each layer through the variation of the resistivity with the depth. Applying the Schumberger array, a total of 48 vertical electrical sounding is conducted along 8 profiles directed W-E and using traditional method, 25 test pits with depth between 15 and 19 meters are done. Qualitative interpretation is carried out through the resistivity and test pit maps. The test pit maps reveal the presence of the following layers: The first layer of thickness varies from 0.2 to 2.0 m (average of 1.9 m). The thickness of the second layer varies between 0.2 and 4.0 m with an average of 2.8 m. The thickness of the third layer is between 2.0 and 4.0 m with an average of 3.8 m. That of the fourth and fifth layers ranges respectively between 4.0 and 6.0 m (average of 5.4 m) and between 2.0 and 6.0 m with an average of 4.4 m. Isoresistivities maps from resistivities computed for different AB/2 values (1.5; 4.4; 13.5; 19; 27.5; 58 m) are generally characterized by the apparent resistivities which define many domains in function of the AB/2 values. The superficial layer is characterized by electric resistivity values ranging from 720 to 2073 Ωm for AB/2 = 1.5 m and probably represents pedologic materials. For other values of AB/2, resistivity varies from 253 to 32,381 Ωm (AB/2 = 4.4 m), 0.1 to 1838 (AB/2 = 13.2 m) with an average of 341 Ωm, 0.3 to 1608 Ωm (AB/2 = 19 m) with an average of 279 Ωm, 6.4 to 1427 Ωm (AB/2 = 27.5 m) with an average 291 Ωm, and 19.7 to 3555 Ωm (AB/2 = 58 m) with an average of 850 Ωm. These different values of resistivity represent the sedimentary materials.

Functions of Conserved Domains of Human Polynucleotide Phosphorylase on RNA Oxidation.

Human polynucleotide phosphorylase (hPNPase), an exoribonuclease that is primarily localized in mitochondria, plays an important role in reducing oxidized RNA and protecting cells under oxidative stress conditions. hPNPase contains two catalytic domains (RPH1 and RPH2) and two RNA binding domains (KH and S1), and an N-terminal mitochondrial translocation signal (MTS). In this study, we examined the potential roles of each domain in hPNPase function on controlling RNA oxidative damage. DNA encoding full-length hPNPase and its domain-deletion mutants were introduced into HeLa cells, and the levels of an oxidized RNA lesion, 8-hydroxyguanosine (8-oxo-Guo) were determined in mitochondrial and cytoplasmic RNA under oxidative stress conditions. Our study showed that the S1 RNA binding domain is crucial for reducing 8-oxo-Guo in both cytoplasm and mitochondria, while the MTS is required for 8-oxo-Guo reduction in mitochondria.

Human primary immunodeficiency caused by expression of a kinase-dead p110δ mutant

This case demonstrates the essential contribution of the p110δ catalytic 21 domain in adaptive immunity function in a patient with expression of a kinase-dead p110δ mutant.

2015년 국가수준 학업성취도 평가의 고등학교 수학과 서답형 문항 분석

The objective of this study is to characterize the academic achievement of students based on an analysis of constructed response items in high school mathematics from the 2015 National Assessment of Educational Achievement(NAEA) to enhance teaching and learning efficiency. Towards this end, the responses of 7,468 students in the sample-based assessment were classified by type and further analyzed in connection with problem-solving process. According to the study results, proficient-level and lower-level students expressed difficulty with determination of points of internal division in a coordinate plane and with analysis of maximum and minimum quadratic functions. Advanced-level students showed insufficient understanding of procedures for formulation of distance between points and lines and methods to calculate maximum and minimum values based on domain in the quadratic function.

Structure of APP-C991–99 and implications for role of extra-membrane domains in function and oligomerization

The 99 amino acid C-terminal fragment of Amyloid Precursor Protein APP-C99 (C99) is cleaved by γ-secretase to form Aβ peptide, which plays a critical role in the etiology of Alzheimer's Disease (AD). The structure of C99 consists of a single transmembrane domain flanked by intra and intercellular domains. While the structure of the transmembrane domain has been well characterized, little is known about the structure of the flanking domains and their role in C99 processing by γ-secretase. To gain insight into the structure of full-length C99, REMD simulations were performed for monomeric C99 in model membranes of varying thickness. We find equilibrium ensembles of C99 from simulation agree with experimentally-inferred residue insertion depths and protein backbone chemical shifts. In thin membranes, the transmembrane domain structure is correlated with extra-membrane structural states and the extra-membrane domain structural states become less correlated to each other. Mean and variance of the transmembrane and G37G38 hinge angles are found to increase with thinning membrane. The N-terminus of C99 forms β-strands that may seed aggregation of Aβ on the membrane surface, promoting amyloid formation. In thicker membranes the N-terminus forms α-helices that interact with the nicastrin domain of γ-secretase. The C-terminus of C99 becomes more α-helical as the membrane thickens, forming structures that may be suitable for binding by cytoplasmic proteins, while C-terminal residues essential to cytotoxic function become α-helical as the membrane thins. The heterogeneous but discrete extra-membrane domain states analyzed here open the path to new investigations of the role of C99 structure and membrane in amyloidogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

Fluorescent protein tagged hepatitis B virus capsid protein with long glycine-serine linker that supports nucleocapsid formation

Fusion core proteins of Hepatitis B virus can be used to study core protein functions or capsid trafficking. A problem in constructing fusion core proteins is functional impairment of the individual domains in these fusion proteins, might due to structural interference. We reported a method to construct fusion proteins of Hepatitis B virus core protein (HBc) in which the functions of fused domains were partially kept. This method follows two principles: (1) fuse heterogeneous proteins at the N terminus of HBc; (2) use long Glycine-serine linkers between the two domains. Using EGFP and RFP as examples, we showed that long flexible G4S linkers can effectively separate the two domains in function. Among these fusion proteins constructed, GFP-G4S186-HBc and RFP-G4S47-HBc showed the best efficiency in rescuing the replication of an HBV replicon deficient in the core protein expression, though both of the two fusion proteins failed to support the formation of the relaxed circular DNA. These fluorescent protein-tagged HBcs might help study related to HBc or capsids tracking in cells.

Mechanical responses of the mechanosensitive unstructured domains in cardiac titin.

Titin is one of the three main filaments in cardiac sarcomere. Besides a chain of Ig domains, cardiac titin also contains a proline (P), glutamate (E), valine (V), lysine (K) (PEVK) domain and a cardiac-specific N2B domain, both are largely unstructured. While they are believed to be involved in the elastic (PEVK and N2B) and the trophic (N2B) functions of the heart, their mechanical responses in physiological level of forces remains poorly understood. In order to gain understanding on their mechanical responses, we used magnetic tweezers to investigate their force responses from 1 to 30pN. We confirmed that in vitro the PEVK domain is intrinsically disordered within the force range. Surprisingly, we discovered a mechanosensitive folded element in the disordered region of N2B, ∼84 amino acids in length, which has a large folding energy of approximately -10 kB T. Based on the force responses of PEVK and N2B domains, as well as an approximated force-dependent unfolding and refolding rates of titin Ig domains, we show that the tension in cardiac titin fluctuates within 5pN during cardiac contraction and extension cycle using Gillespie simulation algorithm. Exceptionally, the simulation shows that deletion of N2B domain results in 10-fold increase in peak force. Our results highlight a critical role that N2B may potentially play in regulating tension on cardiac titin. The study provides new insights into the tension regulatory role of unstructured domains in the elastic function of the heart, which has broad implication in diastolic dysfunction and cardiac trophic mechanisms. In addition, the method can be applied to probing other unstructured mechanosensitive proteins/domains.

A double point mutation at residues Ile14 and Val15 of Bcl-2 uncovers a role for the BH4 domain in both protein stability and function.

B-cell lymphoma 2 (Bcl-2) protein is the archetype apoptosis suppressor protein. The N-terminal Bcl-2-homology 4 (BH4) domain of Bcl-2 is required for the antiapoptotic function of this protein at the mitochondria and endoplasmic reticulum (ER). The involvement of the BH4 domain in Bcl-2's antiapoptotic functions has been proposed based on Gly-based substitutions of the Ile14/Val15 amino acids, two hydrophobic residues located in the center of Bcl-2's BH4 domain. Following this strategy, we recently showed that a BH4-domain-derived peptide in which Ile14 and Val15 have been replaced by Gly residues, was unable to dampen proapoptotic Ca2+ -release events from the ER. Here, we investigated the impact of these mutations on the overall structure, stability, and function of full-length Bcl-2 as a regulator of Ca2+ signaling and cell death. Our results indicate that full-length Bcl-2 Ile14Gly/Val15Gly, in contrast to wild-type Bcl-2, (a) displayed severely reduced structural stability and a shortened protein half-life; (b) failed to interact with Bcl-2-associated X protein (BAX), to inhibit the inositol 1,4,5-trisphosphate receptor (IP3 R) and to protect against Ca2+ -mediated apoptosis. We conclude that the hydrophobic face of Bcl-2's BH4 domain (Ile14, Val15) is an important structural regulatory element by affecting protein stability and turnover, thereby likely reducing Bcl-2's ability to modulate the function of its targets, like IP3 R and BAX. Therefore, Bcl-2 structure/function studies require pre-emptive and reliable determination of protein stability upon introduction of point mutations at the level of the BH4 domain.

Central catalytic domain of BRAP (RNF52) recognizes the types of ubiquitin chains and utilizes oligo-ubiquitin for ubiquitylation.

Really interesting new gene (RING)-finger protein 52 (RNF52), an E3 ubiquitin ligase, is found in eukaryotes from yeast to humans. Human RNF52 is known as breast cancer type 1 susceptibility protein (BRCA1)-associated protein 2 (BRAP or BRAP2). The central catalytic domain of BRAP comprises four subdomains: nucleotide-binding α/β plait (NBP), really interesting new gene (RING) zinc finger, ubiquitin-specific protease (UBP)-like zinc finger (ZfUBP), and coiled-coil (CC). This domain architecture is conserved in RNF52 orthologs; however, the domain's function in the ubiquitin system has not been delineated. In the present study, we discovered that the RNF52 domain, comprising NBP–RING–ZfUBP–CC, binds to ubiquitin chains (oligo-ubiquitin) but not to the ubiquitin monomers, and can utilize various ubiquitin chains for ubiquitylation and auto-ubiquitylation. The RNF52 domain preferentially bound to M1- and K63-linked di-ubiquitin chains, weakly to K27-linked chains, but not to K6-, K11-, or K48-linked chains. The binding preferences of the RNF52 domain for ubiquitin-linkage types corresponded to ubiquitin usage in the ubiquitylation reaction, except for K11-, K29-, and K33-linked chains. Additionally, the RNF52 domain directly ligated the intact M1-linked, tri-, and tetra-ubiquitin chains and recognized the structural alterations caused by the phosphomimetic mutation of these ubiquitin chains. Full-length BRAP had nearly the same specificity for the ubiquitin-chain types as the RNF52 domain alone. Mass spectrometry analysis of oligomeric ubiquitylation products, mediated by the RNF52 domain, revealed that the ubiquitin-linkage types and auto-ubiquitylation sites depend on the length of ubiquitin chains. Here, we propose a model for the oligomeric ubiquitylation process, controlled by the RNF52 domain, which is not a sequential assembly process involving monomers.

RRM domain of Arabidopsis splicing factor SF1 is important for pre-mRNA splicing of a specific set of genes.

The RNA recognition motif of Arabidopsis splicing factor SF1 affects the alternative splicing of FLOWERING LOCUS M pre-mRNA and a heat shock transcription factor HsfA2 pre-mRNA. Splicing factor 1 (SF1) plays a crucial role in 3' splice site recognition by binding directly to the intron branch point. Although plant SF1 proteins possess an RNA recognition motif (RRM) domain that is absent in its fungal and metazoan counterparts, the role of the RRM domain in SF1 function has not been characterized. Here, we show that the RRM domain differentially affects the full function of the Arabidopsis thaliana AtSF1 protein under different experimental conditions. For example, the deletion of RRM domain influences AtSF1-mediated control of flowering time, but not the abscisic acid sensitivity response during seed germination. The alternative splicing of FLOWERING LOCUS M (FLM) pre-mRNA is involved in flowering time control. We found that the RRM domain of AtSF1 protein alters the production of alternatively spliced FLM-β transcripts. We also found that the RRM domain affects the alternative splicing of a heat shock transcription factor HsfA2 pre-mRNA, thereby mediating the heat stress response. Taken together, our results suggest the importance of RRM domain for AtSF1-mediated alternative splicing of a subset of genes involved in the regulation of flowering and adaptation to heat stress.

A role of the SAM domain in EphA2 receptor activation

Among the 20 subfamilies of protein receptor tyrosine kinases (RTKs), Eph receptors are unique in possessing a sterile alpha motif (SAM domain) at their C-terminal ends. However, the functions of SAM domains in Eph receptors remain elusive. Here we report on a combined cell biology and quantitative fluorescence study to investigate the role of the SAM domain in EphA2 function. We observed elevated tyrosine autophosphorylation levels upon deletion of the EphA2 SAM domain (EphA2ΔS) in DU145 and PC3 prostate cancer cells and a skin tumor cell line derived from EphA1/A2 knockout mice. These results suggest that SAM domain deletion induced constitutive activation of EphA2 kinase activity. In order to explain these effects, we applied fluorescence correlation spectroscopy to investigate the lateral molecular organization of EphA2. Our results indicate that SAM domain deletion (EphA2ΔS-GFP) increases oligomerization compared to the full length receptor (EphA2FL-GFP). Stimulation with ephrinA1, a ligand for EphA2, induced further oligomerization and activation of EphA2FL-GFP. The SAM domain deletion mutant, EphA2ΔS-GFP, also underwent further oligomerization upon ephrinA1 stimulation, but the oligomers were larger than those observed for EphA2FL-GFP. Based on these results, we conclude that the EphA2 SAM domain inhibits kinase activity by reducing receptor oligomerization.

Role of the PB2 627 Domain in Influenza A Virus Polymerase Function.

ABSTRACTThe RNA genome of influenza A viruses is transcribed and replicated by the viral RNA-dependent RNA polymerase, composed of the subunits PA, PB1, and PB2. High-resolution structural data revealed that the polymerase assembles into a central polymerase core and several auxiliary highly flexible, protruding domains. The auxiliary PB2 cap-binding and the PA endonuclease domains are both involved in cap snatching, but the role of the auxiliary PB2 627 domain, implicated in host range restriction of influenza A viruses, is still poorly understood. In this study, we used structure-guided truncations of the PB2 subunit to show that a PB2 subunit lacking the 627 domain accumulates in the cell nucleus and assembles into a heterotrimeric polymerase with PB1 and PA. Furthermore, we showed that a recombinant viral polymerase lacking the PB2 627 domain is able to carry out cap snatching, cap-dependent transcription initiation, and cap-independent ApG dinucleotide extension in vitro, indicating that the PB2 627 domain of the influenza virus RNA polymerase is not involved in core catalytic functions of the polymerase. However, in a cellular context, the 627 domain is essential for both transcription and replication. In particular, we showed that the PB2 627 domain is essential for the accumulation of the cRNA replicative intermediate in infected cells. Together, these results further our understanding of the role of the PB2 627 domain in transcription and replication of the influenza virus RNA genome.IMPORTANCE Influenza A viruses are a major global health threat, not only causing disease in both humans and birds but also placing significant strains on economies worldwide. Avian influenza A virus polymerases typically do not function efficiently in mammalian hosts and require adaptive mutations to restore polymerase activity. These adaptations include mutations in the 627 domain of the PB2 subunit of the viral polymerase, but it still remains to be established how these mutations enable host adaptation on a molecular level. In this report, we characterize the role of the 627 domain in polymerase function and offer insights into the replication mechanism of influenza A viruses.

Male infertility-linked point mutation reveals a vital binding role for the C2 domain of sperm PLCζ.

Sperm-specific phospholipase C zeta (PLCζ) is widely considered to be the physiological stimulus that evokes intracellular calcium (Ca2+) oscillations that are essential for the initiation of egg activation during mammalian fertilisation. A recent genetic study reported a male infertility case that was directly associated with a point mutation in the PLCζ C2 domain, where an isoleucine residue had been substituted with a phenylalanine (I489F). Here, we have analysed the effect of this mutation on the in vivo Ca2+ oscillation-inducing activity and the in vitro biochemical properties of human PLCζ. Microinjection of cRNA or recombinant protein corresponding to PLCζI489F mutant at physiological concentrations completely failed to cause Ca2+ oscillations and trigger development. However, this infertile phenotype could be effectively rescued by microinjection of relatively high (non-physiological) amounts of recombinant mutant PLCζI489F protein, leading to Ca2+ oscillations and egg activation. Our in vitro biochemical analysis suggested that the PLCζI489F mutant displayed similar enzymatic properties, but dramatically reduced binding to PI(3)P and PI(5)P-containing liposomes compared with wild-type PLCζ. Our findings highlight the importance of PLCζ at fertilisation and the vital role of the C2 domain in PLCζ function, possibly due to its novel binding characteristics.

Distinct roles for extracellular and intracellular domains in neuroligin function at inhibitory synapses.

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.

Enhanced Cytosolic Ca2+ Activation Underlies a Common Defect of Central Domain Cardiac Ryanodine Receptor Mutations Linked to Arrhythmias

Recent three-dimensional structural studies reveal that the central domain of ryanodine receptor (RyR) serves as a transducer that converts long-range conformational changes into the gating of the channel pore. Interestingly, the central domain encompasses one of the mutation hotspots (corresponding to amino acid residues 3778–4201) that contains a number of cardiac RyR (RyR2) mutations associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) and atrial fibrillation (AF). However, the functional consequences of these central domain RyR2 mutations are not well understood. To gain insights into the impact of the mutation and the role of the central domain in channel function, we generated and characterized eight disease-associated RyR2 mutations in the central domain. We found that all eight central domain RyR2 mutations enhanced the Ca2+-dependent activation of [3H]ryanodine binding, increased cytosolic Ca2+-induced fractional Ca2+ release, and reduced the activation and termination thresholds for spontaneous Ca2+ release in HEK293 cells. We also showed that racemic carvedilol and the non-beta-blocking carvedilol enantiomer, (R)-carvedilol, suppressed spontaneous Ca2+ oscillations in HEK293 cells expressing the central domain RyR2 mutations associated with CPVT and AF. These data indicate that the central domain is an important determinant of cytosolic Ca2+ activation of RyR2. These results also suggest that altered cytosolic Ca2+ activation of RyR2 represents a common defect of RyR2 mutations associated with CPVT and AF, which could potentially be suppressed by carvedilol or (R)-carvedilol.

The Nuclear Protein IκBζ Forms a Transcriptionally Active Complex with Nuclear Factor-κB (NF-κB) p50 and the Lcn2 Promoter via the N- and C-terminal Ankyrin Repeat Motifs

The nuclear protein IκBζ, comprising the N-terminal trans-activation domain and the C-terminal ankyrin repeat (ANK) domain composed of seven ANK motifs, activates transcription of a subset of nuclear factor-κB (NF-κB)-dependent innate immune genes such as Lcn2 encoding the antibacterial protein lipocalin-2. Lcn2 activation requires formation of a complex containing IκBζ and NF-κB p50, a transcription factor that harbors the DNA-binding Rel homology region but lacks a trans-activation domain, on the promoter with the canonical NF-κB-binding site (κB site) and its downstream cytosine-rich element. Here we show that IκBζ productively interacts with p50 via Asp-451 in the N terminus of ANK1, a residue that is evolutionarily conserved among IκBζ and the related nuclear IκB proteins Bcl-3 and IκBNS Threonine substitution for Asp-451 abrogates direct association with the κB-site-binding protein p50, complex formation with the Lcn2 promoter DNA, and activation of Lcn2 transcription. The basic residues Lys-717 and Lys-719 in the C-terminal region of ANK7 contribute to IκBζ binding to the Lcn2 promoter, probably via interaction with the cytosine-rich element required for Lcn2 activation; glutamate substitution for both lysines results in a loss of transcriptionally active complex formation without affecting direct contact of IκBζ with p50. Both termini of the ANK domain in Bcl-3 and IκBNS function in a manner similar to that of IκBζ to interact with promoter DNA, indicating a common mechanism in which the nuclear IκBs form a regulatory complex with NF-κB and promoter DNA via the invariant aspartate in ANK1 and the conserved basic residues in ANK7.

Partial deletion of DEPDC5 in a child with focal epilepsy.

SummaryWe report on a child, aged 47/12 years, with borderline intelligence quotient, normal brain magnetic resonance imaging, and focal epilepsy. The polysomnographic electroencephalogram recording revealed asynchronous central spikes at both brain hemispheres resembling the features observed in focal idiopathic epileptic syndromes. Array comparative genomic hybridization analysis revealed a 32‐kb partial deletion of the DEP domain‐containing protein 5 (DEPDC5) gene, involved in a wide spectrum of inherited focal epileptic syndromes. The parental origin of the deletion could not be fully ascertained because the pregnancy had been achieved through anonymous egg donation and insemination by intracytoplasmic sperm injection. However, we demonstrate that the deletion, shared by all alternatively spliced isoforms of DEPDC5, produces a transcript presumably generating a DEPDC5 protein missing the entire DEP domain. Our findings suggest that partial deletion of DEPDC5 may be sufficient to cause the focal epilepsy in our patient, highlighting the importance of the DEP domain in DEPDC5 function. This study expands the phenotypic spectrum of DEPDC5 to sporadic forms of focal idiopathic epilepsy and underscores the fact that partial deletions, albeit probably very rare, are part of the genetic spectrum of DEPDC5 mutations.

Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly

BackgroundNeurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the...