Mechanism of signal-anchor triage during early steps of membrane protein insertion.

Most membrane proteins use their first transmembrane domain, known as a signal anchor (SA), for co-translational targeting to the endoplasmic reticulum (ER) via the signal recognition particle (SRP). The SA then inserts into the membrane using either the Sec61 translocation channel or the ER membrane protein complex (EMC) insertase. How EMC and Sec61 collaborate to ensure SA insertion in the correct topology is not understood. Using site-specific crosslinking, we detect a pre-insertion SA intermediate adjacent to EMC. This intermediate forms after SA release from SRP but before ribosome transfer to Sec61. The polypeptide's N-terminal tail samples a cytosolic vestibule bordered by EMC3, from where it can translocate across the membrane concomitant with SA insertion. The ribosome then docks on Sec61, which has an opportunity to insert those SAs skipped by EMC. These results suggest that EMC acts between SRP and Sec61 to triage SAs for insertion during membrane protein biogenesis.

The ER membrane protein complex restricts mitophagy by controlling BNIP3 turnover.

Lysosomal degradation of autophagy receptors is a common proxy for selective autophagy. However, we find that two established mitophagy receptors, BNIP3 and BNIP3L/NIX, are constitutively delivered to lysosomes in an autophagy-independent manner. This alternative lysosomal delivery of BNIP3 accounts for nearly all its lysosome-mediated degradation, even upon mitophagy induction. To identify how BNIP3, a tail-anchored protein in the outer mitochondrial membrane, is delivered to lysosomes, we performed a genome-wide CRISPR screen for factors influencing BNIP3 flux. This screen revealed both known modifiers of BNIP3 stability as well as a pronounced reliance on endolysosomal components, including the ER membrane protein complex (EMC). Importantly, the endolysosomal system and the ubiquitin-proteosome system regulated BNIP3 independently. Perturbation of either mechanism is sufficient to modulate BNIP3-associated mitophagy and affect underlying cellular physiology. More broadly, these findings extend recent models for tail-anchored protein quality control and install endosomal trafficking and lysosomal degradation in the canon of pathways that tightly regulate endogenous tail-anchored protein localization.

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex.

Membrane protein biogenesis faces the challenge of chaperoning hydrophobic transmembrane helices for faithful membrane insertion. The guided entry of tail-anchored proteins (GET) pathway targets and inserts tail-anchored (TA) proteins into the endoplasmic reticulum (ER) membrane with an insertase (yeast Get1/Get2 or mammalian WRB/CAML) that captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively). Here, we present cryo-electron microscopy reconstructions, native mass spectrometry, and structure-based mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes. Get3 binding to the membrane insertase supports heterotetramer formation, and phosphatidylinositol binding at the heterotetramer interface stabilizes the insertase for efficient TA insertion in vivo. We identify a Get2/CAML cytoplasmic helix that forms a "gating" interaction with Get3/TRC40 important for TA insertion. Structural homology with YidC and the ER membrane protein complex (EMC) implicates an evolutionarily conserved insertion mechanism for divergent substrates utilizing a hydrophilic groove. Thus, we provide a detailed structural and mechanistic framework to understand TA membrane insertion.

Membrane insertases at a glance.

Protein translocases, such as the bacterial SecY complex, the Sec61 complex of the endoplasmic reticulum (ER) and the mitochondrial translocases, facilitate the transport of proteins across membranes. In addition, they catalyze the insertion of integral membrane proteins into the lipid bilayer. Several membrane insertases cooperate with these translocases, thereby promoting the topogenesis, folding and assembly of membrane proteins. Oxa1 and BamA family members serve as core components in the two major classes of membrane insertases. They facilitate the integration of proteins with α-helical transmembrane domains and of ß-barrel proteins into lipid bilayers, respectively. Members of the Oxa1 family were initially found in the internal membranes of bacteria, mitochondria and chloroplasts. Recent studies, however, also identified several Oxa1-type insertases in the ER, where they serve as catalytically active core subunits in the ER membrane protein complex (EMC), the guided entry of tail-anchored (GET) and the GET- and EMC-like (GEL) complex. The outer membrane of bacteria, mitochondria and chloroplasts contain ß-barrel proteins, which are inserted by members of the BamA family. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of these different types of membrane insertases and discuss their function.

Inhibition of UBA52 induces autophagy via EMC6 to suppress hepatocellular carcinoma tumorigenesis and progression.

Ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52) has a role in the occurrence and development of tumours. However, the mechanism by which UBA52 regulates hepatocellular carcinoma (HCC) tumorigenesis and progression remains poorly understood. By using the Cell Counting Kit (CCK-8), colony formation, wound healing and Transwell assays, we assessed the effects of UBA52 knockdown and overexpression on the proliferation and migration of HCC cells in vitro. By establishing subcutaneous and metastatic tumour models in nude mice, we evaluated the effects of UBA52 on HCC cell proliferation and migration in vivo. Through bioinformatic analysis of data from the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases, we discovered that UBA52 is associated with autophagy. In addition, we discovered that HCC tissues with high UBA52 expression had a poor prognosis in patients. Moreover, knockdown of UBA52 reduced HCC cell growth and metastasis both in vitro and in vivo. Mechanistically, knockdown of UBA52 induced autophagy through EMC6 in HCC cells. These findings suggest that UBA52 promoted the proliferation and migration of HCC cells through autophagy regulation via EMC6 and imply that UBA52 may be a viable novel treatment target for HCC patients.

EMC10 modulates hepatic ER stress and steatosis in an isoform-specific manner.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) membrane protein complex subunit 10 (EMC10) has been implicated in obesity. Here we investigated the roles of the two isoforms of EMC10, including a secreted isoform (scEMC10) and an ER membrane-bound isoform (mEMC10), in metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS: Manifold steatotic mouse models and HepG2 cells were employed to investigate the role of EMC10 in the regulation of hepatic PERK-eIF2α-ATF4 signaling and hepatosteatosis. The therapeutic effect of scEMC10-neutralizing antibody on mouse hepatosteatosis was explored. Associations of MASLD with serum scEMC10 and hepatic mEMC10 were determined in two cohorts of participants with MASLD. RESULTS: scEMC10 promoted, while mEMC10 suppressed, the activation of hepatic PERK-eIF2α-ATF4 signaling. Emc10 gene knockout exacerbated, while hepatic overexpression of mEMC10 ameliorated, hepatic ER stress and steatosis in mice challenged with either a methionine- and choline-deficient diet or tunicamycin, highlighting a direct, suppressive role of mEMC10 in MASLD via modulation of hepatic ER stress. Overexpression of scEMC10 promoted, whereas neutralization of circulating scEMC10 prevented, hepatosteatosis in mice with fatty liver, suggesting a role of scEMC10 in MASLD development. Clinically, serum scEMC10 was increased, while hepatic mEMC10 was decreased, in participants with MASLD. Correlative analysis indicated that serum scEMC10 positively, whereas hepatic mEMC10 negatively, correlated with liver fat content and serum ALT, AST, and GGT. CONCLUSIONS: These findings demonstrate a novel isoform-specific role for EMC10 in the pathogenesis of MASLD and identify the secreted isoform as a tractable therapeutic target for MASLD via antibody-based neutralization. IMPACT AND IMPLICATIONS: We have shown the role of EMC10 in the regulation of energy homeostasis and obesity. In this study, we determine the distinct roles of the two isoforms of EMC10 in the regulation of hepatic endoplasmic reticulum stress and steatosis in mice, and report on the associations of the different EMC10 isoforms with metabolic dysfunction-associated steatotic liver disease in humans. Our findings delineate a novel regulatory axis for hepatosteatosis and identify EMC10 as a modulator of the PERK-eIF2α-ATF4 signaling cascade that may be of broad physiological significance. Moreover, our pre-clinical and clinical studies provide evidence of the therapeutic potential of targeting scEMC10 in MASLD.

Commissioning and initial validation of Eclipse eMC algorithm for the electron FLASH research extension (FLEX) system for pre-clinical studies.

PURPOSE: To investigate the feasibility of commissioning the 16 MeV electron FLASH Extension (FLEX) in the commercial treatment planning system (TPS) for biomedical research with cell and mouse models, and in silico treatment planning studies. METHODS: To commission the FLEX system with the electron Monte Carlo (eMC) algorithm in the commercial TPS, radiochromic film was used to measure the vendor-recommended beam data. Once the beam model was generated for the eMC algorithm, supplemental measurements were collected for validation purposes and compared against the TPS-calculated results. Additionally, the newly commissioned 16 MeV FLASH beam was compared to the corresponding 16 MeV conventional electron beam. RESULTS: The eMC algorithm effectively modeled the FLEX system. The eMC-calculated PDDs and profiles for the 16 MeV electron FLASH beam agreed with measured values within 1%, on average, for 6 × 6 cm2 and 10 × 10 cm2 applicators. Flatness and symmetry deviated by less than 1%, while FWHM and penumbra agreed within 1 mm for both eMC-calculated and measured profiles. Additionally, the small field (i.e., 2-cm diameter cutout) that was measured for validation purposes agreed with TPS-calculated results within 1%, on average, for both the PDD and profiles. The FLASH and conventional dose rate 16 MeV electron beam were in agreement in regard to energy, but the profiles for larger field sizes began to deviate (>10 × 10 cm2) due to the forward-peaked nature of the FLASH beam. For cell irradiation experiments, the measured and eMC-calculated in-plane and cross-plane absolute dose profiles agreed within 1%, on average. CONCLUSIONS: The FLEX system was successfully commissioned in the commercial TPS using the eMC algorithm, which accurately modeled the forward-peaked nature of the FLASH beam. A commissioned TPS for FLASH will be useful for pre-clinical cell and animal studies, as well as in silico FLASH treatment planning studies for future clinical implementation.

Helmholtz Plane Regulation Empowers PF6- Permselectivity towards High Coulombic Efficiency Dual Ion Battery of 5.5 V.

High-voltage dual ion battery (DIB) is promising for stationary energy storage applications owing to its cost-effectiveness, which has been a hot topic of research in rechargeable battery fields. However, it still suffers from rapid battery failure caused by the severe solvent co-intercalation and electrolyte oxidation. To address these bottlenecks, herein a functional electrolyte additive hexafluoroglutaric anhydride (HFGA) is presented based on a Helmholtz plane regulation strategy. It is demonstrated that the HFGA can precisely enter into the Helmholtz plane and positively regulate anion solvation behaviors near the graphite electrode surface owing to its considerable H-F affinity with ethyl methyl carbonate (EMC), thus alleviating EMC-related co-intercalation and oxidation decomposition during DIB charging. Meanwhile, HFGA can copolymerize with the presence of PF5 at the Helmholtz plane to participate in forming a CF2-rich CEI layer with excellent PF6- permselectivity, conducive to achieving PF6- de-solvation and simultaneously suppressing electrolyte oxidation decomposition. By virtue of such beneficial effects, the graphite cathode enables a 5.5 V DIB with a prominent capacity retention of 92% and a high average Coulombic efficiency exceeding 99% within 2000 cycles, demonstrating significantly enhanced electrochemical reversibility. The Helmholtz plane regulation strategy marks a milestone in advancing DIB technologies.

Expanding EMC foldopathies: Topogenesis deficits alter the neural crest.

The endoplasmic reticulum (ER) membrane protein complex (EMC) is essential for the insertion of a wide variety of transmembrane proteins into the plasma membrane across cell types. Each EMC is composed of Emc1-7, Emc10, and either Emc8 or Emc9. Recent human genetics studies have implicated variants in EMC genes as the basis for a group of human congenital diseases. The patient phenotypes are varied but appear to affect a subset of tissues more prominently than others. Namely, craniofacial development seems to be commonly affected. We previously developed an array of assays in Xenopus tropicalis to assess the effects of emc1 depletion on the neural crest, craniofacial cartilage, and neuromuscular function. We sought to extend this approach to additional EMC components identified in patients with congenital malformations. Through this approach, we determine that EMC9 and EMC10 are important for neural crest development and the development of craniofacial structures. The phenotypes observed in patients and our Xenopus model phenotypes similar to EMC1 loss of function likely due to a similar mechanism of dysfunction in transmembrane protein topogenesis.

Sequence-based features that are determinant for tail-anchored membrane protein sorting in eukaryotes.

The correct targeting and insertion of tail-anchored (TA) integral membrane proteins is critical for cellular homeostasis. TA proteins are defined by a hydrophobic transmembrane domain (TMD) at their C-terminus and are targeted to either the ER or mitochondria. Derived from experimental measurements of a few TA proteins, there has been little examination of the TMD features that determine localization. As a result, the localization of many TA proteins are misclassified by the simple heuristic of overall hydrophobicity. Because ER-directed TMDs favor arrangement of hydrophobic residues to one side, we sought to explore the role of geometric hydrophobic properties. By curating TA proteins with experimentally determined localizations and assessing hypotheses for recognition, we bioinformatically and experimentally verify that a hydrophobic face is the most accurate singular metric for separating ER and mitochondria-destined yeast TA proteins. A metric focusing on an 11 residue segment of the TMD performs well when classifying human TA proteins. The most inclusive predictor uses both hydrophobicity and C-terminal charge in tandem. This work provides context for previous observations and opens the door for more detailed mechanistic experiments to determine the molecular factors driving this recognition.

Compound heterozygous splicing variants expand the genotypic spectrum of EMC1-related disorders.

EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders.

Cyathocotylidae spp and motile aeromonads co-infections in farmed Nile tilapia (Oreochromis niloticus) causing mass mortality.

Motile aeromonads, and Cyathocotylidaespp.co-infections were identified in farmed Nile tilapia(Oreochromis niloticus) which suffering from mortalities. Moribund fish showed signs of septicemia, skin irritations, and respiratory distress. A total of 150 O. niloticus specimens showing signs of disease were collected from the affected earthmen ponds and examined. Bacteriological examination of fish samples revealed infections with motile aeromonads species. Phenotypic characteristics and phylogenetic analysis of gyrB gene sequences of aeromonads isolates identified them as Aeromonas hydrophila (12.6%), A.sobria (12.6%), and A. caviae (30.4%). Aeromonads strains harbored some virulence genes: Aer (78.62%); Hyl (60.86%); laf-A (52.17%); and Act (47.82%). The antibiogram of aeromonads showed high resistance against tetracycline (73.9%), and gentamycin (65.2%), while a high sensitivity was noticed to ciprofloxacin (82.6%),and trimethoprim/sulfamethoxazole (60.86%). Parasitological examination of fish revealed the presence of Cyathocotylidae spp. encysted metacercaria (EMC). High levels of interleukin 6 (IL-6) and cluster of differentiation 4 (CD4) were noticed in fish with parasitic and bacterial co-infection compared to those with a single infection or non-infected. Experimentally infected fish with Aeromonas spp. showed septicemic signs similar to that noticed in naturally infected tilapia with variable cumulative mortality. The study is one of the earlier reports identifying as Cyathocotylidae spp., and motile aeromonads co-infections, and their link with the exaggerated tilapia mortality which will be of value for incorporating these pathogens in the necessary management strategies to protect fish health.

Effects of surface curvature on electron Monte Carlo (eMC) calculation results.

Some clinical situations in radiotherapy require electron beams to be incident on curved patient surfaces. This study presents central-axis dose output (cGy/MU) and percent dose versus depth (PDD) data that show the effects of curvature on results computed by the Varian eMC v15.6 algorithm using 6, 9, 12, 16, and 20 MeV electron beams incident on virtual phantoms with curved surfaces. The phantoms were designed to simulate common treatment sites. The dose outputs at the depth of maximum dose (dmax) on the central axis were observed to decrease 0%-14%, and several features of the PDDs for the A10 applicator changed, including up to 12% increased entrance dose. These dosimetric changes have the greatest effect on treatment sites with a radius of curvature of 10 cm or less, such as the scalp, nose, neck, and extremities. The concept of applying a curvature correction factor based on relative output data is presented to help clinical users mitigate discrepancies between calculations performed by simple monitor unit verification systems and accurate treatment planning dose algorithms.

Squaring the EMC - how promoting membrane protein biogenesis impacts cellular functions and organismal homeostasis.

Integral membrane proteins play key functional roles at organelles and the plasma membrane, necessitating their efficient and accurate biogenesis to ensure appropriate targeting and activity. The endoplasmic reticulum membrane protein complex (EMC) has recently emerged as an important eukaryotic complex for biogenesis of integral membrane proteins by promoting insertion and stability of atypical and sub-optimal transmembrane domains (TMDs). Although confirmed as a bona fide complex almost a decade ago, light is just now being shed on the mechanism and selectivity underlying the cellular responsibilities of the EMC. In this Review, we revisit the myriad of functions attributed the EMC through the lens of these new mechanistic insights, to address questions of the cellular and organismal roles the EMC has evolved to undertake.

Switchable Broadband-to-Tunable Narrowband Magnetic Probe for Near-Field Measurements.

This paper presents a printed magnetic probe that can switch from broadband to tunable narrowband for near-field measurement. In the early design stage, we created a printed loop gap resonator as a magnetic reference sensor for the pre-compliance test in a band up to 6 GHz. Consequently, the results showed a good response in terms of the S11 and S21 parameters of the proposed probe compared with the commercial magnetic sensor XF-R 3-1. The source noise might spread among different frequency bands, making the broadband magnetic probe the closest choice for estimating the magnetic field in the near-field region. Unfortunately, broadband magnetic probes have lower sensitivity than narrowband ones. One of the solutions to get high sensitivity is to connect the LNA to the output of the passive magnetic sensor. This work proposes a novel method to solve this issue using a PIN diode to change the broadband status into a high sensitivity narrowband status and then tune this narrowband across the most critical applications such as 3.5 GHz, 3.75 GHz, 4.8 GHz, and 5.2 GHz with the help of a varactor diode. Compared to the broadband status, an improvement of more than 10 dB has been obtained across all these wireless bands. Furthermore, the proposed structure's isolation between the electrical and magnetic fields is about 13 dB.

Membrane-Bound EMC10 Is Required for Sperm Motility via Maintaining the Homeostasis of Cytoplasm Sodium in Sperm.

Endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is an evolutionarily conserved and multifunctional factor across species. We previously reported that Emc10 knockout (KO) leads to mouse male infertility. Emc10-null spermatozoa exhibit multiple aspects of dysfunction, including reduced sperm motility. Two subunits of a Na/K-ATPase, ATP1A4 and ATP1B3, are nearly absent in Emc10 KO spermatozoa. Here, two isoforms of EMC10 were characterized in the mouse testis and epididymis: the membrane-bound (mEMC10) and secreted (scEMC10) isoforms. We present evidence that mEMC10, rather than scEMC10, is required for cytoplasm sodium homeostasis by positively regulating ATP1B3 expression in germ cells. Intra-testis mEMC10 overexpression rescued the sperm motility defect caused by Emc10 KO, while exogenous recombinant scEMC10 protein could not improve the motility of spermatozoa from either Emc10 KO mouse or asthenospermic subjects. Clinically, there is a positive association between ATP1B3 and EMC10 protein levels in human spermatozoa, whereas no correlation was proven between seminal plasma scEMC10 levels and sperm motility. These results highlight the important role of the membrane-bound EMC10 isoform in maintaining cytoplasm sodium homeostasis and sperm motility. Based on the present results, the mEMC10-Na, K/ATPase α4ß3 axis is proposed as a novel mechanism underlying the regulation of cytoplasmic sodium and sperm motility, and its components seem to have therapeutic potential for asthenospermia.

The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis.

The eukaryotic endoplasmic reticulum (ER) membrane contains essential complexes that oversee protein biogenesis and lipid metabolism, impacting nearly all aspects of cell physiology. The ER membrane protein complex (EMC) is a newly described transmembrane domain (TMD) insertase linked with various phenotypes, but whose clients and cellular responsibilities remain incompletely understood. We report that EMC deficiency limits the cellular boundaries defining cholesterol tolerance, reflected by diminished viability with limiting or excessive extracellular cholesterol. Lipidomic and proteomic analyses revealed defective biogenesis and concomitant loss of the TMD-containing ER-resident enzymes sterol-O-acyltransferase 1 (SOAT1) and squalene synthase (SQS, also known as FDFT1), which serve strategic roles in the adaptation of cells to changes in cholesterol availability. Insertion of the weakly hydrophobic tail-anchor (TA) of SQS into the ER membrane by the EMC ensures sufficient flux through the sterol biosynthetic pathway while biogenesis of polytopic SOAT1 promoted by the EMC provides cells with the ability to store free cholesterol as inert cholesteryl esters. By facilitating insertion of TMDs that permit essential mammalian sterol-regulating enzymes to mature accurately, the EMC is an important biogenic determinant of cellular robustness to fluctuations in cholesterol availability.This article has an associated First Person interview with the first author of the paper.

PEA Electromagnetic Distortion Reduction by Impedance Grounding and Pulsed Voltage Electrode Configurations.

Space charges are one of the main challenges facing the constantly increasing use of extruded high voltage direct current (HVDC) cables. The Pulsed Electro-Acoustic (PEA) method is one of the most common procedures for space charge measurements of insulation. One issue with the PEA method is distortion due to the crosstalk between the applied voltage pulse and the acoustic sensor. This work analyzed two factors involved in the reduction in this distortion: the influence of the exposed semiconductor distance between the injection electrodes and PEA test cell, and the influence of adding a reactance at the grounding circuit of the PEA test cell. The interaction of these two factors with the distortion was analyzed through a series of experimental testing. Moreover, the performance regarding distortion after applying a developed coaxial injection was compared with the standard non-coaxial injection configuration. It was observed that these two factors had a direct impact on distortion and can be utilized for the reduction in distortion arising from the crosstalk of the applied pulsed voltage. The results can be utilized for the consideration of practical aspects during the construction of a PEA test setup for the measurement of full-size HVDC cables.

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum.

Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades taught us one humble lesson: no one size fits all. Cells use an impressive array of components to enable the safe transport of protein cargo from the cytosolic ribosomes to the endoplasmic reticulum. Safety during the transit is warranted by the interplay of cytosolic chaperones, membrane receptors, and protein translocases that together form functional networks and serve as protein targeting and translocation routes. While two targeting routes to the endoplasmic reticulum, SRP (signal recognition particle) and GET (guided entry of tail-anchored proteins), prefer targeting determinants at the N- and C-terminus of the cargo polypeptide, respectively, the recently discovered SND (SRP-independent) route seems to preferentially cater for cargos with non-generic targeting signals that are less hydrophobic or more distant from the termini. With an emphasis on targeting routes and protein translocases, we will discuss those functional networks that drive efficient protein topogenesis and shed light on their redundant and dynamic nature in health and disease.

EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay.

In recent years, several genes have been implicated in the variable disease presentation of global developmental delay (GDD) and intellectual disability (ID). The endoplasmic reticulum membrane protein complex (EMC) family is known to be involved in GDD and ID. Homozygous variants of EMC1 are associated with GDD, scoliosis, and cerebellar atrophy, indicating the relevance of this pathway for neurogenetic disorders. EMC10 is a bone marrow-derived angiogenic growth factor that plays an important role in infarct vascularization and promoting tissue repair. However, this gene has not been previously associated with human disease. Herein, we describe a Saudi family with two individuals segregating a recessive neurodevelopmental disorder. Both of the affected individuals showed mild ID, speech delay, and GDD. Whole-exome sequencing (WES) and Sanger sequencing were performed to identify candidate genes. Further, to elucidate the functional effects of the variant, quantitative real-time PCR (RT-qPCR)-based expression analysis was performed. WES revealed a homozygous splice acceptor site variant (c.679-1G>A) in EMC10 (chromosome 19q13.33) that segregated perfectly within the family. RT-qPCR showed a substantial decrease in the relative EMC10 gene expression in the patients, indicating the pathogenicity of the identified variant. For the first time in the literature, the EMC10 gene variant was associated with mild ID, speech delay, and GDD. Thus, this gene plays a key role in developmental milestones, with the potential to cause neurodevelopmental disorders in humans.