Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome.
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ABSTRACT:
SUBMITTER: Kane MS
PROVIDER: S-EPMC5841196 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionVici syndrome (also known as immunodeficiency with cleft lip/palate, cataract, and hypopigmentation and absent corpus callosum) is considered as a progressive neurodevelopmental multisystem disorder. Till date, only 80 cases, including our patient, with this syndrome have been reported .This syndrome is characterized by agenesis of the corpus callosum, hypopigmentation of the eyes and hair, cataract, cardiomyopathy, combined immunodeficiency, hearing loss, seizures, and additional multisystem involvements which have been reported as case reports in the past. Clinical Manifestation. A 5-year-old girl, who is a product of consanguineous marriage, was referred to our center with developmental delay, optic atrophy, blindness, spasticity, seizure, movement disability, and spasticity. Her magnetic resonance imaging (MRI) test showed agenesis of the corpus callosum and her metabolic test reported normal.Materials and methodsIn our laboratory, blood sample was obtained from the patient. DNA was extracted from lymphocytes, and whole exome sequencing (WES) using next generation Illumina sequencing was performed.ResultA novel (private), homozygous, nonsynonymous mutation c.A3206G (p.Y1069C Het) in EPG5 gene was detected; in continuum, testing for this specific variant in her parents was carried out. DNA sequencing of the PCR-amplified product of the EPG5 exon 17 showed that her parents were heterozygote for this variant. These mutations have not been reported before and therefore classified as variation of unknown significance (VUS). Mutation in this gene is shown to cause autosomal recessive Vici syndrome.ConclusionSince clinical features of Vici syndrome has overlap, its diagnosis is differential and developmental delay occurs in 98% of reported cases. Vici syndrome can be considered as one of the main causes of developmental delay, and this syndrome can be introduced as a novel group of inherited neurometabolic conditions and congenital disorders.
| S-EPMC9277209 | biostudies-literature
Project description:Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.
| S-EPMC4766378 | biostudies-literature
Project description:Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.
| S-EPMC4012842 | biostudies-literature
Project description:Autophagy helps to maintain cellular homeostasis by removing misfolded proteins and damaged organelles, and generally acts as a cytoprotective mechanism for neuronal survival. Here we showed that mice deficient in the Vici syndrome gene Epg5, which is required for autophagosome maturation, show accumulation of ubiquitin-positive inclusions and SQSTM1 aggregates in various retinal cell types. In epg5-/- retinas, photoreceptor function is greatly impaired, and degenerative features including progressively reduced numbers of photoreceptor cells and increased numbers of apoptotic cells in the outer nuclear layer are observed, while the morphology of other parts of the retina is not severely affected. Downstream targets of the unfolded protein response (UPR), including the death inducer DDIT3/CHOP, and also levels of cleaved CASP3 (caspase 3), are elevated in epg5-/- retinas. Thus, apoptotic photoreceptor cell death in epg5-/- retinas may result from the elevated UPR. Our results reveal that Epg5-deficient mice recapitulate key characteristics of retinitis pigmentosa and thus may provide a valuable model for investigating the molecular mechanism of photoreceptor degeneration.
| S-EPMC5173265 | biostudies-literature
Project description:The EPG5 protein is a RAB7A effector involved in fusion specificity between autophagosomes and late endosomes or lysosomes during macroautophagy/autophagy. Mutations in the human EPG5 gene cause a rare and severe multisystem disorder called Vici syndrome. In this work, we show that zebrafish epg5-/- mutants from both heterozygous and incrossed homozygous matings are viable and can develop to the age of sexual maturity without conspicuous defects in external appearance. In agreement with the dysfunctional autophagy of Vici syndrome, western blot revealed higher levels of the Lc3-II autophagy marker in epg5-/- mutants with respect to wild type controls. Moreover, starvation elicited higher accumulation of Lc3-II in epg5-/- than in wild type larvae, together with a significant reduction of skeletal muscle birefringence. Accordingly, muscle ultrastructural analysis revealed accumulation of degradation-defective autolysosomes in starved epg5-/- mutants. By aging, epg5-/- mutants showed impaired motility and muscle thinning, together with accumulation of non-degradative autophagic vacuoles. Furthermore, epg5-/- adults displayed morphological alterations in gonads and heart. These findings point at the zebrafish epg5 mutant as a valuable model for EPG5-related disorders, thus providing a new tool for dissecting the contribution of EPG5 on the onset and progression of Vici syndrome as well as for the screening of autophagy-stimulating drugs. Abbreviations: ATG: autophagy related; cDNA: complementary DNA; DIG: digoxigenin; dpf: days post-fertilization; EGFP: enhanced green fluorescent protein; EPG: ectopic P granules; GFP: green fluorescent protein; hpf: hours post-fertilization; IL1B: interleukin 1 beta; Lc3-II: lipidated Lc3; mpf: months post-fertilization; mRNA: messenger RNA; NMD: nonsense-mediated mRNA decay; PCR: polymerase chain reaction; qPCR: real time-polymerase chain reaction; RAB7A/RAB7: RAB7a, member RAS oncogene family; RACE: rapid amplification of cDNA ends; RFP: red fluorescent protein; RT-PCR: reverse transcriptase-polymerase chain reaction; SEM: standard error of the mean; sgRNA: guide RNA; UTR: untranslated region; WMISH: whole mount in situ hybridization; WT: wild type.
| S-EPMC6613882 | biostudies-literature
Project description:Vici syndrome is a rare, congenital disorder that affects multiple systems and is caused by mutations in the EPG5 gene that encodes for ectopic P-granules autophagy protein 5 (EPG5). The induced pluripotent stem cell (iPSC) line described here was generated from a dermal fibroblast cell line from an 8-year-old male donor with a homozygous recessive c.1007A>G (p.Q336R) mutation in the EPG5 gene. This iPSC model of Vici syndrome provides a unique and valuable resource for investigators to study the pathology of EPG5 mutations and the aetiology of the disease as well as develop therapeutic treatments for those with Vici syndrome.
| S-EPMC9375524 | biostudies-literature
Project description:Vici syndrome is a human inherited multi-system disorder caused by recessive mutations in EPG5, encoding the EPG5 protein that mediates the fusion of autophagosomes with lysosomes. Immunodeficiency characterized by lack of memory B cells and increased susceptibility to infection is an integral part of the condition, but the role of EPG5 in the immune system remains unknown. Here we show that EPG5 is indispensable for the transport of the TLR9 ligand CpG to the late endosomal-lysosomal compartment, and for TLR9-initiated signaling, a step essential for the survival of human memory B cells and their ultimate differentiation into plasma cells. Moreover, the predicted structure of EPG5 includes a membrane remodeling domain and a karyopherin-like domain, thus explaining its function as a carrier between separate vesicular compartments. Our findings indicate that EPG5, by controlling nucleic acids intracellular trafficking, links macroautophagy/autophagy to innate and adaptive immunity.
| S-EPMC5846549 | biostudies-literature
Project description:Mutations in the autophagy gene EPG5 are linked to the multisystem human disease Vici syndrome, which is characterized in part by pulmonary abnormalities, including recurrent infections. We found that Epg5-deficient mice exhibited elevated baseline innate immune cellular and cytokine-based lung inflammation and were resistant to lethal influenza virus infection. Lung transcriptomics, bone marrow transplantation experiments, and analysis of cellular cytokine expression indicated that Epg5 plays a role in lung physiology through its function in macrophages. Deletion of other autophagy genes including Atg14, Fip200, Atg5, and Atg7 in myeloid cells also led to elevated basal lung inflammation and influenza resistance. This suggests that Epg5 and other Atg genes function in macrophages to limit innate immune inflammation in the lung. Disruption of this normal homeostatic dampening of lung inflammation results in increased resistance to influenza, suggesting that normal homeostatic mechanisms that limit basal tissue inflammation support some infectious diseases.
| S-EPMC4714358 | biostudies-literature
Project description:Platelets mediate central aspects of host responses during sepsis, an acute profoundly systemic inflammatory response due to infection. Macroautophagy/autophagy, which mediates critical aspects of cellular responses during inflammatory conditions, is known to be a functional cellular process in anucleate platelets, and is essential for normal platelet functions. Nevertheless, how sepsis may alter autophagy in platelets has never been established. Using platelets isolated from septic patients and matched healthy controls, we show that during clinical sepsis, the number of autophagosomes is increased in platelets, most likely due to an accumulation of autophagosomes, some containing mitochondria and indicative of mitophagy. Therefore, autophagy induction or early-stage autophagosome formation (as compared to decreased later-stage autophagosome maturation or autophagosome-late endosome/lysosome fusion) is normal or increased. This was consistent with decreased fusion of autophagosomes with lysosomes in platelets. EPG5 (ectopic P-granules autophagy protein 5 homolog), a protein essential for normal autophagy, expression did increase, while protein-protein interactions between EPG5 and MAP1LC3/LC3 (which orchestrate the fusion of autophagosomes and lysosomes) were significantly reduced in platelets during sepsis. Furthermore, data from a megakaryocyte model demonstrate the importance of TLR4 (toll like receptor 4), LPS-dependent signaling for regulating this mechanism. Similar phenotypes were also observed in platelets isolated from a patient with Vici syndrome: an inherited condition caused by a naturally occurring, loss-of-function mutation in EPG5. Together, we provide evidence that autophagic functions are aberrant in platelets during sepsis, due in part to reduced EPG5-LC3 interactions, regulated by TLR4 engagement, and the resultant accumulation of autophagosomes.Abbreviations: ACTB: beta actin; CLP: cecal ligation and puncture; Co-IP: co-immunoprecipitation; DAP: death associated protein; DMSO: dimethyl sulfoxide; EPG5: ectopic P-granules autophagy protein 5 homolog; ECL: enhanced chemiluminescence; HBSS: Hanks' balanced salt solution; HRP: horseradish peroxidase; ICU: intensive care unit; LPS: lipopolysaccharide; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MKs: megakaryocytes; PFA: paraformaldehyde; PBS: phosphate-buffered saline; PLA: proximity ligation assay; pRT-PCR: quantitative real-time polymerase chain reaction; RT: room temperature; SQSTM1/p62: sequestosome 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TLR4: toll like receptor 4; TEM: transmission electron microscopy; WGA: wheat germ agglutinin.
| S-EPMC9298447 | biostudies-literature
Project description: Not available
| S-EPMC3925270 | biostudies-literature