ABSTRACT
Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.
Subject(s)
Cockayne Syndrome , Induced Pluripotent Stem Cells , Oligodendroglia , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/pathology , Cockayne Syndrome/genetics , Cockayne Syndrome/metabolism , Cockayne Syndrome/pathology , Oligodendroglia/metabolism , Oligodendroglia/cytology , Cell Movement , DNA Repair Enzymes/metabolism , DNA Repair Enzymes/genetics , Neurons/metabolism , Neurons/pathology , Autophagy , Brain/metabolism , Brain/pathology , Poly-ADP-Ribose Binding Proteins/metabolism , Poly-ADP-Ribose Binding Proteins/genetics , gamma-Aminobutyric Acid/metabolism , DNA Helicases/metabolism , DNA Helicases/genetics , Microcephaly/pathology , Microcephaly/metabolism , Microcephaly/genetics , Demyelinating Diseases/pathology , Demyelinating Diseases/metabolism , Cell DifferentiationABSTRACT
Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading to early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein IER3IP1 plays a non-essential role in ER-Golgi transport. Here, we employed secretome and cell-surface proteomics to demonstrate that the absence of IER3IP1 results in the mistrafficking of proteins crucial for neuronal development and survival, including FGFR3, UNC5B and SEMA4D. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL-receptor 2 are compromised, with the latter leading to the anomalous secretion of ER-localized chaperones. Our investigation extended to in-utero knock-down of Ier3ip1 in mouse embryo brains, revealing a morphological phenotype in newborn neurons. In summary, our findings provide insights into how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome.
Subject(s)
Endoplasmic Reticulum , Golgi Apparatus , Microcephaly , Endoplasmic Reticulum/metabolism , Animals , Microcephaly/genetics , Microcephaly/metabolism , Microcephaly/pathology , Mice , Golgi Apparatus/metabolism , Humans , Mutation , Protein Transport , Membrane Proteins/metabolism , Membrane Proteins/genetics , Neurons/metabolism , Neurons/pathologyABSTRACT
BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation is a rare autosomal dominant disease caused by mutations in KIF11 which disrupt EG5 protein function, impacting the development and maintenance of retinal and lymphatic structures due to its expression in the retinal photoreceptor cilia. The primary ocular finding in MCLMR is chorioretinopathy. Additional features can include microphthalmia, angle-closure glaucoma, persistent hyperplastic primary vitreous, cataract, pseudo-coloboma, persistent hyaloid artery, and myopic or hypermetropic astigmatism. The appearance of the chorioretinal lesions as white to pinkish, round, non-elevated atrophic areas devoid of blood vessels resembles the lacunae in Aicardy syndrome. Due to the lack of systematic description of the lesions and significant phenotypical variability, there is an impending need for a detailed report of each case. CASE PRESENTATION: A child with microcephaly detected in the third trimester of gestation began her following in the ophthalmology department due to a non-visually significant cataract. Shortly after, she developed nystagmus and large-angle alternating esotropia with cross-fixation. Her fundus initially showed a pallid optic disc and pigmentary changes, developing thereafter retinal lacunae and a retinal fold. Her differential diagnosis accompanied the dynamic changes in her fundus, which included congenital infections, Leber´s Congenital Amaurosis and Aicardy syndrome. At 19 months old, genetic testing identified a heterozygous mutation (c.1159 C > T, p.Arg387*) in the KIF11 gene. The patient underwent bilateral medial rectus muscle recession surgery at 2 years old for persistent esotropia, with significant improvement. Refraction revealed a hyperopic astigmatism in both eyes (+ 0.25 -2.50 × 180 OD and + 0.75 -2.00 × 170 OS). She continues to require right eye patching for 2 hours daily. CONCLUSIONS: This case report expands the phenotypic spectrum of MCLMR by demonstrating a unique combination of retinal features which sheds new light on differential diagnosis from Aicardy syndrome. Our findings emphasize the significant phenotypic variability associated with MCLMR, particularly regarding ocular involvement. This underscores the importance of detailed clinical evaluation and comprehensive reporting of cases to improve our understanding of the disease spectrum and genotype-phenotype correlations.
Subject(s)
Intellectual Disability , Lymphedema , Microcephaly , Humans , Microcephaly/genetics , Microcephaly/diagnosis , Female , Lymphedema/genetics , Lymphedema/diagnosis , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retinal Dysplasia , Kinesins , FaciesABSTRACT
This review aimed to provide an update on the morphological and/or functional abnormalities related to congenital Zika virus (ZIKV) infection, based on primary data from studies conducted in Brazil since 2015. During the epidemic years (2015-2016), case series and pediatric cohort studies described several birth defects, including severe and/or disproportionate microcephaly, cranial bone overlap, skull collapse, congenital contractures (arthrogryposis and/or clubfoot), and visual and hearing abnormalities, as part of the spectrum of Congenital Zika Syndrome (CZS). Brain imaging abnormalities, mainly cortical atrophy, ventriculomegaly, and calcifications, serve as structural markers of CZS severity. Most case series and cohorts of microcephaly have reported the co-occurrence of epilepsy, dysphagia, orthopedic deformities, motor function impairment, cerebral palsy, and urological impairment. A previous large meta-analysis conducted in Brazil revealed that a confirmed ZIKV infection during pregnancy was associated with a 4% risk of microcephaly. Additionally, one-third of children showed at least one abnormality, predominantly identified in isolation. Studies examining antenatally ZIKV-exposed children without detectable abnormalities at birth reported conflicting neurodevelopmental results. Therefore, long-term follow-up studies involving pediatric cohorts with appropriate control groups are needed to address this knowledge gap. We recognize the crucial role of a national network of scientists collaborating with international research institutions in understanding the lifelong consequences of congenital ZIKV infection. Additionally, we highlight the need to provide sustainable resources for research and development to reduce the risk of future Zika outbreaks.
Subject(s)
Microcephaly , Pregnancy Complications, Infectious , Zika Virus Infection , Zika Virus Infection/congenital , Zika Virus Infection/complications , Zika Virus Infection/epidemiology , Humans , Brazil/epidemiology , Pregnancy , Female , Microcephaly/virology , Microcephaly/epidemiology , Pregnancy Complications, Infectious/epidemiology , Pregnancy Complications, Infectious/virology , Infant, NewbornABSTRACT
Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
Subject(s)
Developmental Disabilities , Intellectual Disability , Microcephaly , Animals , Child , Child, Preschool , Female , Humans , Male , Mice , Chlorocebus aethiops , COS Cells , Developmental Disabilities/genetics , HEK293 Cells , Intellectual Disability/genetics , Microcephaly/genetics , Microcephaly/pathology , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Zebrafish/geneticsABSTRACT
BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare genetic condition resulting in multiple congenital anomalies, including facial dysmorphism, structural anomalies of the internal organs, functional disorders, and, although less commonly, ocular abnormalities. To present a child with MWS and eye abnormalities. METHODS: A 3-year-old boy was born at 37 weeks of pregnancy with dysmorphic features, neurodevelopmental disorders, genetically confirmed MWS, nystagmus, strabismus, and suspicion of congenital glaucoma. Ophthalmic examination was carried out under general anesthesia; eyeball ultrasound and electrophysiological examination (flash visual evoked potentials) were also performed. RESULTS: The examinations revealed nystagmus, a normal response of pupils to light in both eyes, and normal intraocular pressure, that is, 17 and 18â mmâ Hg in the right and left eye, respectively. Corneal thickness was 606 µm in the right eye and 588 µm in the left eye. Gonioscopy revealed displacement of Schwalbe line anterior to the limbus of the cornea (posterior embryotoxon). Fundus examination revealed a pink optic disk with a cup-to-disc ratio of 0.5, macular pigment regrouping, and normal blood vessels. Flash visual evoked potentials: P2 latency was normal. P2 amplitude from the left hemisphere was reduced to 50%, and P2 amplitude over the right hemisphere was normal. CONCLUSION: Children with genetically determined congenital anomalies need regular ophthalmic checkups to accurately assess the eye and determine the prospects of vision function development.
Subject(s)
Hirschsprung Disease , Intellectual Disability , Microcephaly , Humans , Male , Child, Preschool , Microcephaly/genetics , Microcephaly/diagnosis , Intellectual Disability/genetics , Hirschsprung Disease/genetics , Hirschsprung Disease/diagnosis , Hirschsprung Disease/physiopathology , Facies , Evoked Potentials, Visual/physiology , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Eye Abnormalities/physiopathologyABSTRACT
O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant genetic disorder caused by mutations in the KMT2E (lysine methyltransferase 2E) gene. The Third Xiangya Hospital of Central South University admitted a 12-year and 9-month-old male patient who presented with growth retardation, intellectual disability, and distinctive facial features. Peripheral blood was collected from the patient, and DNA was extracted for genetic testing. Chromosome karyotyping showed 46XY. Whole-exome sequencing and low-coverage massively parallel copy number variation sequencing (CNV-seq) revealed a 506 kb heterozygous deletion in the 7q22.3 region, which includes 6 genes, including KMT2E. The patient was diagnosed with ODLURO syndrome. Both the patient's parents and younger brother had normal clinical phenotypes and genetic test results, indicating that this deletion was a de novo mutation. The clinical and genetic characteristics of this case can help increase clinicians' awareness of ODLURO syndrome.
Subject(s)
Intellectual Disability , Humans , Male , Intellectual Disability/genetics , Child , Histone-Lysine N-Methyltransferase/genetics , Mutation , Growth Disorders/genetics , Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 7/genetics , Karyotyping , Phenotype , DNA Copy Number Variations , Exome Sequencing , Heterozygote , Contracture , Microcephaly , FaciesABSTRACT
Objective: To summarize the genotype and clinical phenotype of children with WWOX gene related developmental and epileptic encephalopathy (DEE). Methods: Case series studies. The clinical data of 12 children with WWOX gene related DEE who were admitted to the Neurological Department of Children's Medical Center, Peking University First Hospital from June 2019 to December 2023 were analyzed. The children's characteristics of gene variation, clinical phenotype, auxiliary examination results, treatment and prognosis were analyzed. Results: Among 12 children with WWOX gene related DEE, there were 7 boys and 5 girls, the age of seizure onset ranged from 10 days to 6 months (median 1.8 months). Multiple seizure types were observed, including focal seizures in 10 cases, epileptic spasms in 9 cases, tonic seizures in 4 cases, myoclonic seizures in 1 case. Among 12 cases, 9 cases had multiple seizure types. All 12 cases showed microcephaly and global developmental delay. Video electroencephalography showed slowed background activity in 6 cases, hyperarrhythmia in 6 cases, multifocal discharges in 6 cases, and focal discharges in 1 case. Epileptic spasms were detected in 8 cases, tonic seizures in 4 cases and myoclonic seizures in 1 case. Brain magnetic resonance imaging showed bilateral frontotemporal subarachnoid space widening in 5 cases, deep sulci in 3 cases, bilateral ventricular enlargement in 2 cases, callosal hypoplasia in 5 cases, and delayed white matter myelination in 3 cases. The phenotypes of 12 cases were consistent with the diagnosis of DEE, and 8 of them were diagnosed with infantile epileptic spasm syndrome. All the WWOX gene variants in 12 cases were complex heterozygous variants, including 20 variants, 11 variants and 1 large intragenic WWOX gene deletion (p.Ala149Thr, p.Arg156Ser, p.R167Tfs*8, p.Leu186Val, c.605+5G>A, p.Trp218*, p.His263Arg, p.Leu275fs*19*1, p.N285Kfs*10, p.Ser304Tyr, p.Met326Arg, loss1 exon2-8) had not been reported previously. The age of last follow-up ranged from 11 months to 5 years and 3 months. During the follow-up, 1 case died at the age of 1 year and 10 months, 2 cases were seizure-free, and 9 cases still had seizures after multiple anti-seizure medications. Conclusions: The seizure onset age of children with WWOX gene related DEE is usually less than 6 months, and some of them in neonate. The common seizure types include focal seizures and epileptic spasms. Children usually have microcephaly and global developmental delay. WWOX gene related DEE usually has drug refractory epilepsy.
Subject(s)
Electroencephalography , Genotype , Mutation , Phenotype , WW Domain-Containing Oxidoreductase , Humans , WW Domain-Containing Oxidoreductase/genetics , Male , Female , Infant , Spasms, Infantile/genetics , Epilepsy/genetics , Epilepsy/diagnosis , Infant, Newborn , Magnetic Resonance Imaging , Seizures/genetics , Microcephaly/genetics , Developmental Disabilities/genetics , Child, Preschool , Tumor Suppressor Proteins/geneticsABSTRACT
Oropouche virus could be linked to brain malformation and stillbirths, Brazilian health officials say.
Subject(s)
Brain , Bunyaviridae Infections , Infectious Disease Transmission, Vertical , Microcephaly , Orthobunyavirus , Stillbirth , Female , Humans , Pregnancy , Brain/abnormalities , Brain/virology , Brazil/epidemiology , Fetus/virology , Stillbirth/epidemiology , Bunyaviridae Infections/epidemiology , Microcephaly/virologyABSTRACT
Structural variation is a source of genetic variation that, in some cases, may trigger pathogenicity. Here, we describe two cases, a mother and son, with the same partial inverted duplication of the long arm of chromosome 8 [invdup(8)(q24.21q24.21)] of 17.18 Mb, showing different clinical manifestations: microcephaly, dorsal hypertrichosis, seizures and neuropsychomotor development delay in the child, and a cleft lip/palate, down-slanted palpebral fissures and learning disabilities in the mother. The deleterious outcome, in general, is reflected by the gain or loss of genetic material. However, discrepancies among the clinical manifestations raise some concerns about the genomic configuration within the chromosome and other genetic modifiers. With that in mind, we also performed a literature review of research published in the last 20 years about the duplication of the same, or close, chromosome region, seeking the elucidation of at least some relevant clinical features.
Subject(s)
Chromosomes, Human, Pair 8 , Humans , Female , Male , Chromosomes, Human, Pair 8/genetics , Adult , Chromosome Inversion/genetics , Microcephaly/genetics , Microcephaly/pathology , Chromosome Duplication/genetics , Child , Child, PreschoolABSTRACT
Congenital Zika syndrome (CZS) is a major concern in India and highlights the multifaceted challenges posed by the Zika virus (ZIKV). The alarming increase in CZS cases in India, a condition that has serious effects on both public health and newborns, has raised concerns. This review highlights the importance of raising concern and awareness and taking preventive measures by studying the epidemiology, clinical symptoms, and potential long-term consequences of CZS. The review also contributes to worldwide research and information sharing to improve the understanding and prevention of CZS. As India deals with the changing nature of CZS, this thorough review is an important tool for policymakers, health workers, and researchers to understand what is happening now, plan for what to do in the future, and work together as a team, using medical knowledge, community involvement, and study projects to protect newborns' health and reduce the public health impact of these syndromes.
Subject(s)
Pregnancy Complications, Infectious , Zika Virus Infection , Humans , Zika Virus Infection/epidemiology , Zika Virus Infection/congenital , Zika Virus Infection/prevention & control , Zika Virus Infection/complications , India/epidemiology , Pregnancy , Infant, Newborn , Pregnancy Complications, Infectious/epidemiology , Pregnancy Complications, Infectious/prevention & control , Female , Zika Virus , Microcephaly/epidemiology , Microcephaly/virology , Microcephaly/etiologyABSTRACT
BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental and genetically heterogeneous disorder, characterized by small cranium size (> - 3 SD below mean) and often results in varying degree of intellectual disability. Thirty genes have been identified for the etiology of this disorder due to its clinical and genetic heterogeneity. METHODS AND RESULTS: Here, we report two consanguineous Pakistani families affected with MCPH exhibiting mutation in WDR62 gene. The investigation approach involved Next Generation Sequencing (NGS) gene panel sequencing coupled with linkage analysis followed by validation of identified variants through automated Sanger sequencing and Barcode-Tagged (BT) sequencing. The molecular genetic analysis revealed one novel splice site variant (NM_001083961.2(WDR62):c.1372-1del) in Family A and one known exonic variant NM_001083961.2(WDR62):c.3936dup (p.Val1313Argfs*18) in Family B. Magnetic Resonance Imaging (MRI) scans were also employed to gain insights into the structural architecture of affected individuals. Neurological assessments showed the reduced gyral and sulcal patterns along with normal corpus callosum in affected individuals harboring novel variant. In silico assessments of the identified variants were conducted using different tools to confirm the pathogenicity of these variants. Through In silico analyses, both variants were identified as disease causing and protein modeling of exonic variant indicates subtle conformational alterations in prophesied protein structure. CONCLUSION: This study identifies a novel variant (c.1372-1del) and a recurrent pathogenic variant c.3936dup (p.Val1313Argfs*18) in the WDR62 gene among the Pakistani population, expanding the mutation spectrum for MCPH. These findings emphasize the importance of genetic counseling and awareness to reduce consanguinity and address the burden of this disorder.
Subject(s)
Consanguinity , Microcephaly , Mutation , Nerve Tissue Proteins , Pedigree , Humans , Microcephaly/genetics , Female , Male , Pakistan , Mutation/genetics , Nerve Tissue Proteins/genetics , Neuroimaging/methods , Child , Magnetic Resonance Imaging/methods , High-Throughput Nucleotide Sequencing/methods , Child, Preschool , Adolescent , Cell Cycle ProteinsABSTRACT
Homozygous VPS50 variants have been previously described in two unrelated patients with a neurodevelopmental disorder with microcephaly, seizures and neonatal cholestasis. VPS50 encodes a subunit that is unique to the heterotetrameric endosome-associated recycling protein (EARP) complex. The other subunits of the EARP complex, such as VPS51, VPS52 and VPS53, are also shared by the Golgi-associated retrograde protein complex. We report on an 18-month-old female patient with biallelic VPS50 variants. She carried a paternally inherited heterozygous nonsense c.13A>T; p.(Lys5*) variant. By long-read genome sequencing, we characterised a structural variant with a 4.3 Mb inversion flanked by deletions at both breakpoints on the maternal allele. The ~428 kb deletion at the telomeric inversion breakpoint encompasses the entire VPS50 gene. We demonstrated a deficiency of VPS50 in patient-derived fibroblasts, confirming the loss-of-function nature of both VPS50 variants. VPS53 and VPS52 protein levels were significantly reduced and absent, respectively, in fibroblasts of the patient. These data show that VPS50 and/or EARP deficiency and the associated functional defects underlie the phenotype in patients with VPS50 pathogenic variants. The VPS50-related core phenotype comprises severe developmental delay, postnatal microcephaly, hypoplastic corpus callosum, neonatal low gamma-glutamyl transpeptidase cholestasis and failure to thrive. The disease is potentially fatal in early childhood.
Subject(s)
Codon, Nonsense , Vesicular Transport Proteins , Humans , Female , Infant , Codon, Nonsense/genetics , Vesicular Transport Proteins/genetics , Microcephaly/genetics , Microcephaly/pathology , Phenotype , Cholestasis/genetics , Cholestasis/pathology , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathologyABSTRACT
Background: Genetic microcephaly is linked to an increased risk of developmental disabilities, epilepsy, and motor impairment. The aim of this study is to describe the spectrum of identifiable genetic etiologies, clinical characteristics, and radiologic features of genetic microcephaly in patients referred to a tertiary center in Saudi Arabia. Method: This is a retrospective chart review study of all patients with identifiable genetic microcephaly presenting to a tertiary center in Saudi Arabia. The patients' demographics, clinical, laboratory, radiologic, and molecular findings were collected. Results: Of the total 128 cases referred, 52 cases (40%) had identifiable genetic causes. Monogenic disorders were found in 48 cases (92%), whereas chromosomal disorders were found in only 4 cases (8%). Developmental disability was observed in 40 cases (84%), whereas only 8 cases (16%) had borderline IQ or mild developmental delay. Epilepsy was seen in 29 cases (56%), and motor impairment was seen in 26 cases (50%). Brain magnetic resonance imaging (MRI) revealed abnormalities in 26 (50%) of the cohort. Hereditary neurometabolic disorders were seen in 7 (15%) of the 48 cases with monogenic disorders. The most common gene defect was ASPM, which is responsible for primary microcephaly type 5 and was seen in 10 cases (19%). A novel PLK1 gene pathogenic mutation was seen in 3 cases (6%). Conclusion: Single gene defect is common in this Saudi population, with the ASPM gene being the most common. Hereditary neurometabolic disorders are a common cause of genetic microcephaly. Furthermore, we propose the PKL1 gene mutation as a possible novel cause of genetic microcephaly.
Subject(s)
Microcephaly , Humans , Microcephaly/genetics , Saudi Arabia , Male , Female , Retrospective Studies , Child, Preschool , Child , Infant , Adolescent , Nerve Tissue Proteins/genetics , Magnetic Resonance Imaging , Developmental Disabilities/genetics , Epilepsy/genetics , Mutation/genetics , Brain/diagnostic imaging , Brain/pathologyABSTRACT
INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with a multifaceted etiology. This case report explores the ischemic cryptogenic vascular dissection as a potential underlying cause of ASD. METHODS: A 9-year-old child presented with symptoms of ASD, including social interaction difficulties, repetitive behaviors, and cognitive challenges. Despite conventional ASD treatments, significant improvement was only observed after addressing an underlying ischemic cryptogenic vascular dissection identified through DCE-CT. RESULTS: Following a reconstructive treatment approach to the vascular dissection, the patient showed marked improvement in cognitive functions, social abilities, and a reduction in ASD-related symptoms whether during the perioperative period or during approximately 5-month follow-up. CONCLUSION: This case suggests that ischemic cryptogenic vascular dissection may contribute to the symptoms of ASD. Identifying and treating underlying vascular anomalies may offer a new avenue for mitigating ASD symptoms, emphasizing the need for comprehensive diagnostic estimations in ASD management.
Subject(s)
Autism Spectrum Disorder , Humans , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/complications , Child , Male , Microcephaly/complications , Microcephaly/diagnosisABSTRACT
Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.
Subject(s)
Brain , Mice, Knockout , Neural Stem Cells , Nonsense Mediated mRNA Decay , Tumor Suppressor Protein p53 , Animals , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Mice , Brain/metabolism , Neural Stem Cells/metabolism , Nonsense Mediated mRNA Decay/genetics , Epistasis, Genetic , Microcephaly/genetics , Cell Cycle/physiology , Cell Cycle/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/geneticsABSTRACT
MCPH1 has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of Mcph1 in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of Mcph1 resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as Satb2 and Cdkn1c, was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized Mcph1 knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in Mcph1 knockout MEFs, and silencing p19Arf restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly.
Subject(s)
Cell Cycle Checkpoints , Cellular Senescence , Cyclin-Dependent Kinase Inhibitor p16 , Microcephaly , Animals , Mice , Cell Cycle Checkpoints/genetics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cellular Senescence/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Cyclin-Dependent Kinase Inhibitor p16/deficiency , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Fibroblasts/metabolism , Mice, Knockout , Microcephaly/genetics , Microcephaly/metabolism , Microcephaly/pathologyABSTRACT
Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.
Subject(s)
Cell Cycle Proteins , Intellectual Disability , Microcephaly , Pedigree , Humans , Microcephaly/genetics , Intellectual Disability/genetics , Male , Female , Cell Cycle Proteins/genetics , Adult , Chromosomal Proteins, Non-Histone/genetics , Nerve Tissue Proteins/genetics , Cell Division/genetics , Mutation , Intracellular Signaling Peptides and Proteins/genetics , Genomics , Young Adult , Consanguinity , Exome Sequencing , Homozygote , Developmental Disabilities/genetics , Adolescent , Pakistan , Microtubule-Associated ProteinsABSTRACT
AIM: Nijmegen breakage syndrome (NBS) is an autosomal recessive DNA repair disorder which is characterized by immunodeficiency and increased risk of lymphoproliferative malignancy. CASE: We observed an increase in the rate of chromosomal rearrangements in the cultured cells following an incidental radiograph for craniosynostosis in a newborn who was followed up due to microcephaly. We identified a homozygous deletion of c.657_661delACAAA/p.Lys219fs (rs587776650) in the NBN gene through whole exome sequencing. CONCLUSION: It is crucial to thoroughly examine the clinical features of newborns with microcephaly and consider chromosomal instability syndromes just like Nijmegen breakage syndrome. Not overlooking radiosensitivity, which is a characteristic feature of this syndrome, is a vital condition to the patient's survival time.
Subject(s)
Microcephaly , Nijmegen Breakage Syndrome , Radiation Tolerance , Humans , Nijmegen Breakage Syndrome/genetics , Infant, Newborn , Radiation Tolerance/genetics , Microcephaly/genetics , Cell Cycle Proteins/genetics , Nuclear Proteins/genetics , Male , Exome Sequencing/methods , Female , HomozygoteABSTRACT
Entosis, a form of cell cannibalism, is a newly discovered pathogenic mechanism leading to the development of small brains, termed microcephaly, in which P53 activation was found to play a major role. Microcephaly with entosis, found in Pals1 mutant mice, displays P53 activation that promotes entosis and apoptotic cell death. This previously unappreciated pathogenic mechanism represents a novel cellular dynamic in dividing cortical progenitors which is responsible for cell loss. To date, various recent models of microcephaly have bolstered the importance of P53 activation in cell death leading to microcephaly. P53 activation caused by mitotic delay or DNA damage manifests apoptotic cell death which can be suppressed by P53 removal in these animal models. Such genetic studies attest P53 activation as quality control meant to eliminate genomically unfit cells with minimal involvement in the actual function of microcephaly associated genes. In this review, we summarize the known role of P53 activation in a variety of microcephaly models and introduce a novel mechanism wherein entotic cell cannibalism in neural progenitors is triggered by P53 activation.