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KIF1A-associated neurological disorder (KAND) is a neurodegenerative and often lethal ultrarare disease with a wide phenotypic spectrum associated with largely heterozygous de novo missense variants in KIF1A. Antisense oligonucleotide treatments represent a promising approach for personalized treatments in ultrarare diseases. Here we report the case of one patient with a severe form of KAND characterized by refractory spells of behavioral arrest and carrying a p.Pro305Leu variant in KIF1A, who was treated with intrathecal injections of an allele-specific antisense oligonucleotide specifically designed to degrade the mRNA from the pathogenic allele. The first intrathecal administration was complicated by an epidural cerebrospinal fluid collection, which resolved spontaneously. Otherwise, the antisense oligonucleotide was safe and well tolerated over the 9-month treatment. Most outcome measures, including severity of the spells of behavioral arrest, number of falls and quality of life, improved. There was little change in the 6-min Walk Test distance, but qualitative changes in gait resulting in meaningful reductions in falls and increasing independence were observed. Cognitive performance was stable and did not degenerate over time. Our findings provide preliminary insights on the safety and efficacy of an allele-specific antisense oligonucleotide as a possible treatment for KAND.
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PURPOSE: Transient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women. METHODS: We report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples. RESULTS: Analysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%) and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women. CONCLUSION: This work enriches the phenotypic and genetic description of this recently described disease, and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.
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Anoctamins are a family of Ca2+-activated proteins that may act as ion channels and/or phospholipid scramblases with limited understanding of function and disease association. Here, we identified five de novo and two inherited missense variants in ANO4 (alias TMEM16D) as a cause of fever-sensitive developmental and epileptic or epileptic encephalopathy (DEE/EE) and generalized epilepsy with febrile seizures plus (GEFS+) or temporal lobe epilepsy. In silico modeling of the ANO4 structure predicted that all identified variants lead to destabilization of the ANO4 structure. Four variants are localized close to the Ca2+ binding sites of ANO4, suggesting impaired protein function. Variant mapping to the protein topology suggests a preliminary genotype-phenotype correlation. Moreover, the observation of a heterozygous ANO4 deletion in a healthy individual suggests a dysfunctional protein as disease mechanism rather than haploinsufficiency. To test this hypothesis, we examined mutant ANO4 functional properties in a heterologous expression system by patch-clamp recordings, immunocytochemistry, and surface expression of annexin A5 as a measure of phosphatidylserine scramblase activity. All ANO4 variants showed severe loss of ion channel function and DEE/EE associated variants presented mild loss of surface expression due to impaired plasma membrane trafficking. Increased levels of Ca2+-independent annexin A5 at the cell surface suggested an increased apoptosis rate in DEE-mutant expressing cells, but no changes in Ca2+-dependent scramblase activity were observed. Co-transfection with ANO4 wild-type suggested a dominant-negative effect. In summary, we expand the genetic base for both encephalopathic sporadic and inherited fever-sensitive epilepsies and link germline variants in ANO4 to a hereditary disease.
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Anoctaminas , Mutación Missense , Humanos , Anoctaminas/genética , Anoctaminas/metabolismo , Mutación Missense/genética , Masculino , Femenino , Epilepsia/genética , Niño , Proteínas de Transferencia de Fosfolípidos/genética , Proteínas de Transferencia de Fosfolípidos/metabolismo , Estudios de Asociación Genética , Linaje , Calcio/metabolismo , Genes Dominantes , Preescolar , Células HEK293 , AdolescenteRESUMEN
BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.
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PURPOSE: The purpose of this study was to characterize the phenotype associated with a de novo gain-of-function variant in the GUCY1A2 gene. METHODS: An individual carrying the de novo heterozygous variant c.1458G>T p.(E486D) in GUCY1A2 was identified by exome sequencing. The effect of the corresponding enzyme variant α2E486D/ß1 was evaluated using concentration-response measurements with wild-type enzyme and the variant in cytosolic fractions of HEK293 cells, UV-vis absorbance spectra of the corresponding purified enzymes, and examination of overexpressed fluorescent protein-tagged constructs by confocal laser scanning microscopy. RESULTS: The patient presented with precocious peripheral puberty resembling the autonomous ovarian puberty seen in McCune-Albright syndrome. Additionally, the patient displayed severe intellectual disability. In vitro activity assays revealed an increased nitric oxide affinity for the mutant enzyme. The response to carbon monoxide was unchanged, while thermostability was decreased compared to wild type. Heme content, susceptibility to oxidation, and subcellular localization upon overexpression were unchanged. CONCLUSION: Our data define a syndromic autonomous ovarian puberty likely due to the activating allele p.(E486D) in GUCY1A2 leading to an increase in cGMP. The overlap with the ovarian symptoms of McCune-Albright syndrome suggests an impact of this cGMP increase on the cAMP pathway in the ovary. Additional cases will be needed to ensure a causal link.
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Displasia Fibrosa Poliostótica , Pubertad Precoz , Femenino , Humanos , Displasia Fibrosa Poliostótica/diagnóstico , Mutación con Ganancia de Función , Células HEK293 , Ovario , Pubertad Precoz/etiologíaRESUMEN
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.
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BACKGROUND: Children with neurodevelopmental disorders (NDDs) often have poor oral health and dental abnormalities. An increasing number of genes have been associated with neurodevelopmental conditions affecting the oral cavity, but the specific dental features associated with many genes remain unknown. AIM: To report the types and frequencies of dental manifestations in children with neurodevelopmental conditions of known genetic cause. DESIGN: A 30-question survey assesing ectodermal and dental features was administered through Simons Searchlight, with which formed a recontactable cohort of individuals with genetic NDDs often associated with autism spectrum disorder (ASD). RESULTS: Data were collected from a largely paediatric population with 620 affected individuals across 39 genetic conditions and 145 unaffected siblings without NDDs for comparison. Drooling, difficulty accessing dental care, late primary teeth eruption, abnormal primary and permanent teeth formation, misshapen nails, and hair loss were more frequent in individuals with NDDs. Additionally, we evidenced an association between three new pathogenic gene variant/oral manifestation pairs: CSNK2A1/unusual primary teeth, DYRK1A/late primary teeth eruption, and PPP2R5D/sialorrhea. CONCLUSION: Our results demonstrate that genetic NDDs caused by mutations in CSNK2A1, DYRK1A, and PP2R5D are associated with unique dental manifestations, and knowledge of these features can be helpful to personalize dental care.
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Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Niño , Humanos , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/genética , Cuidadores , Dentición Permanente , Salud Bucal , Proteína Fosfatasa 2RESUMEN
In this case study, we report the case of a 13-year-old girl with citrullinemia type 1 (MIM #215700), an autosomal recessive inherited disorder of the urea cycle, which was confirmed by the identification of a homozygous pathogenic variant in the argininosuccinate synthetase 1 (ASS1) gene. However, the patient presented abnormal hyperkinetic movements with global developmental delay and clinical signs that were not fully consistent with those of citrullinemia type 1 or with those of her siblings with isolated citrullinemia type 1. Exome sequencing showed the presence of a de novo heterozygous pathogenic variant in the adenylate cyclase type 5 (ADCY5) gene. The variant confirmed the overlap with the so-called ADCY5-related dyskinesia with orofacial involvement, which is autosomal dominant (MIM #606703), a disorder disrupting the enzymatic conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). In addition to the citrullinemia-related low-protein diet and arginine supplementation, the identification of this second disease led to the introduction of a treatment with caffeine, which considerably improved the dyskinesia neurological picture. In conclusion, this case highlights the importance of clinical-biological confrontation for the interpretation of genetic variants, as one hereditary metabolic disease may hide another with therapeutic consequences. Summary: This article reports the misleading superposition of two inherited metabolic diseases, showing the importance of clinical-biological confrontation in the interpretation of genetic variants.
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Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.
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Mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3) encodes the c-Jun-amino-terminal kinase-interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole-exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency.
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Atrofia Muscular Espinal , Enfermedades Musculares , Anomalías Musculoesqueléticas , Humanos , Hipotonía Muscular/diagnóstico , Hipotonía Muscular/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patología , Fenotipo , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
BACKGROUND: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a congenital disorder of glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and those responsible for life-threatening bleeding events have never been investigated. OBJECTIVES: To assess platelet functions in patients with XMEN disease. METHODS: Two unrelated young boys, including one before and after hematopoietic stem cell transplantation, were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans. RESULTS: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIbß3 activation, calcium mobilization, and protein kinase C activity were impaired between both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide were absent at both low and high concentrations. These defects were also associated with decreased molecular weights of glycoprotein Ibα, glycoprotein VI, and integrin αIIb due to partial impairment of N-glycosylation. All these defects were corrected after hematopoietic stem cell transplantation. CONCLUSION: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and defective N-glycosylation in several platelet proteins that could explain the hemorrhages reported in patients with XMEN disease.
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Infecciones por Virus de Epstein-Barr , Magnesio , Masculino , Humanos , Magnesio/metabolismo , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Glicosilación , Herpesvirus Humano 4/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismoRESUMEN
Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%-10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US. Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel. Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV. Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.
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Mutations in the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA biology. The TEFM gene encodes the mitochondrial transcription elongation factor responsible for enhancing the processivity of mitochondrial RNA polymerase, POLRMT. We report for the first time that TEFM variants are associated with mitochondrial respiratory chain deficiency and a wide range of clinical presentations including mitochondrial myopathy with a treatable neuromuscular transmission defect. Mechanistically, we show muscle and primary fibroblasts from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts. Finally, tefm knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function, strengthening the genotype-phenotype correlation. Our study highlights that TEFM regulates mitochondrial transcription elongation and its defect results in variable, tissue-specific neurological and neuromuscular symptoms.
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Factores de Transcripción , Pez Cebra , Niño , Animales , Humanos , Factores de Transcripción/genética , ARN Mitocondrial , Pez Cebra/genética , Pez Cebra/metabolismo , ADN Mitocondrial/genética , Transcripción Genética , Mutación , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismoRESUMEN
Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism and frequent infections in humans. Mice genetically lacking Slc30a7 suffer from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing variants or mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. Here, we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia and bone marrow failure. Exome sequencing revealed compound heterozygous variants in ZNT7 consisting of NM_133496.5:c.21dup; p.Asp8ArgfsTer3 and c.842 + 15 T > C inherited from their unaffected mother and father, respectively. The c.21dup variant led to a premature stop codon generated in exon 1 of the ZNT7 coding sequence. RNA-seq analysis demonstrated that the c.842 + 15 T > C variant resulted in a leaky mRNA splicing event generating a premature stop codon right after the splicing donor site of exon 8. Moreover, the expression of ZNT7 protein was remarkably reduced by 80-96% in the affected brothers compared to the control cells. These findings strongly suggest that biallelic variants in SLC30A7 should be considered as a cause of growth retardation, testicular hypoplasia and syndromic bone marrow failure.
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Proteínas de Transporte de Catión , Hipogonadismo , Masculino , Humanos , Ratones , Animales , Hermanos , Codón sin Sentido , Trastornos de Fallo de la Médula Ósea , Hipogonadismo/genética , Zinc/metabolismo , Trastornos del Crecimiento , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismoRESUMEN
Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Fenotipo , Trastornos del Neurodesarrollo/genética , Mutación Missense , Proteínas Portadoras/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
[This corrects the article DOI: 10.1016/j.xhgg.2022.100102.].
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Vesicle biogenesis, trafficking and signaling via Endoplasmic reticulum-Golgi network support essential developmental processes and their disruption lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation. Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding. Functional analysis demonstrates variably disruptive consequences of ARF3 variants on Golgi morphology, vesicles assembly and trafficking. Disease modeling in zebrafish validates further the dominant behavior of the mutants and their differential impact on brain and body plan formation, recapitulating the variable disease expression. In-depth in vivo analyses traces back impaired neural precursors' proliferation and planar cell polarity-dependent cell movements as the earliest detectable effects. Our findings document a key role of ARF3 in Golgi function and demonstrate its pleiotropic impact on development.
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Trastornos del Neurodesarrollo , Pez Cebra , Humanos , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Factores de Ribosilacion-ADP/metabolismo , Aparato de Golgi/metabolismo , Retículo Endoplásmico/metabolismo , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismoRESUMEN
Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] in the eukaryotic initiation factor 5A (eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes. Pathogenic variants affecting either DHPS or EIF5A have been previously associated with neurodevelopmental disorders. Using trio exome sequencing, we identified rare bi-allelic pathogenic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly. A two-dimensional gel analyses revealed the accumulation of deoxyhypusine-containing eIF5A [eIF5A(Dhp)] and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants. Our data suggest that rare bi-allelic variants in DOHH result in reduced enzyme activity, limit the hypusination of eIF5A, and thereby lead to a neurodevelopmental disorder.
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Lisina , Oxigenasas de Función Mixta , Trastornos del Neurodesarrollo , Alelos , Expresión Génica , Humanos , Lisina/análogos & derivados , Oxigenasas de Función Mixta/genética , Trastornos del Neurodesarrollo/genéticaRESUMEN
Congenital heart disease affects around 1% of live births worldwide and can be associated with a wide range of neurodevelopmental disorders. Genetic factors are a major risk factor for poorer neurodevelopmental outcomes. Recent studies have highlighted the complexity of the underlying genetic contributions, including monogenic, oligogenic, and polygenic factors, and their interrelatedness with other risk factors such as preoperative factors (preterm birth, extracardiac malformation, and low birth weight), perioperative factors (anesthesia, type of surgery use of extracorporeal membrane oxygenation, cyanosis, and length of stay in the intensive care unit), postoperative factors (function of the heart after the surgery), and psychosocial factors (socioeconomic status or parent education).