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Genesis (New York, N.Y. : 2000) Jul 2022The Aristaless-related homeobox (ARX) is a paired-like homeodomain transcription factor playing important roles in brain development. Patients with mutations in ARX have...
The Aristaless-related homeobox (ARX) is a paired-like homeodomain transcription factor playing important roles in brain development. Patients with mutations in ARX have a spectrum of neurodevelopmental disorders such as epilepsy, intellectual disability, and autism spectrum disorder, with or without structural abnormalities of the brain such as lissencephaly (smooth brain), microcephaly (small brain), and/or agenesis of the corpus callosum. Mouse models have provided important clues on the pathophysiologic roles of ARX in these disorders. However, successfully isolating specific in vivo complexes of ARX, with DNA and proteins, has remained as a challenge. To facilitate in vivo detection of ARX complexes, we generated a mouse line containing one epitope of FLAG-tag (1 × FLAG) targeted at the translational start site of the endogenous Arx gene using CRSPR/Cas9 strategy. Homozygous Flag-Arx mice are viable and fertile without gross abnormality, suggesting that the FLAG-tag does not perturb the normal function of ARX. Using a FLAG antibody, we successfully detected ARX with immunofluorescent staining and pulled down ARX in embryonic brain tissues. This Flag-Arx mouse line will be a useful tool to isolate ARX complexes from mouse tissues for many applications.
Topics: Animals; Autism Spectrum Disorder; Disease Models, Animal; Genes, Homeobox; Homeodomain Proteins; Intellectual Disability; Mice; Mutation; Transcription Factors
PubMed: 35656878
DOI: 10.1002/dvg.23479 -
European Journal of Human Genetics :... Jan 2024Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one...
Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.
Topics: Humans; Caspase 2; Lissencephaly; Alleles; Neurodevelopmental Disorders; Codon, Nonsense; Phenotype; Cysteine Endopeptidases
PubMed: 37880421
DOI: 10.1038/s41431-023-01461-2 -
Genetics in Medicine : Official Journal... Jul 2023Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase...
PURPOSE
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene.
METHODS
Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences.
RESULTS
We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model.
CONCLUSION
The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.
Topics: Humans; Infant; Fibroblasts; Genetic Diseases, Inborn; HEK293 Cells; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins; Multiprotein Complexes; Mutation, Missense; TOR Serine-Threonine Kinases
PubMed: 37057673
DOI: 10.1016/j.gim.2023.100838 -
ELife Jan 2022The lissencephaly 1 gene, , is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key...
The lissencephaly 1 gene, , is mutated in patients with the neurodevelopmental disease lissencephaly. The Lis1 protein is conserved from fungi to mammals and is a key regulator of cytoplasmic dynein-1, the major minus-end-directed microtubule motor in many eukaryotes. Lis1 is the only dynein regulator known to bind directly to dynein's motor domain, and by doing so alters dynein's mechanochemistry. Lis1 is required for the formation of fully active dynein complexes, which also contain essential cofactors: dynactin and an activating adaptor. Here, we report the first high-resolution structure of the yeast dynein-Lis1 complex. Our 3.1 Å structure reveals, in molecular detail, the major contacts between dynein and Lis1 and between Lis1's ß-propellers. Structure-guided mutations in Lis1 and dynein show that these contacts are required for Lis1's ability to form fully active human dynein complexes and to regulate yeast dynein's mechanochemistry and in vivo function.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Cytoplasmic Dyneins; Dyneins; Gene Expression Regulation; Microtubule-Associated Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 34994688
DOI: 10.7554/eLife.71229 -
JNMA; Journal of the Nepal Medical... Nov 2022Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The...
UNLABELLED
Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The lissencephaly spectrum consists of agyria, pachygyria, and subcortical band heterotopia. At least 19 genes have been identified in the causation of lissencephaly and related syndrome. Lissencephaly is associated with many other congenital disorders but the association of lissencephaly with congenital hypothyroidism is rarely reported. We report a case of a 10-year-old girl having lissencephaly with congenital hypothyroidism. Early diagnosis of lissencephaly and genetic counselling can be made in suspected cases and further possible interventions can be taken. Also, regular follow-up, monitoring, and better conservative management lead to a better prognosis.
KEYWORDS
congenital abnormalities; hypothyroidism; lissencephaly; neuronal migration disorders.
Topics: Female; Humans; Child; Congenital Hypothyroidism; Lissencephaly; Classical Lissencephalies and Subcortical Band Heterotopias; Phenotype
PubMed: 36705174
DOI: 10.31729/jnma.7893 -
Seizure Mar 2024The DYNC1H1 variants are associated with abnormal brain morphology and neuromuscular disorders that are accompanied by epilepsy. This study aimed to explore the...
OBJECTIVES
The DYNC1H1 variants are associated with abnormal brain morphology and neuromuscular disorders that are accompanied by epilepsy. This study aimed to explore the relationship between DYNC1H1 variants and epilepsy.
MATERIALS AND METHODS
Trios-based whole-exome sequencing was performed on patients with epilepsy. Previously reported epilepsy-related DYNC1H1 variants were systematically reviewed to analyse genotype-phenotype correlation.
RESULTS
The DYNC1H1 variants were identified in four unrelated cases of infant-onset epilepsy, including two de novo and two biallelic variants. Two patients harbouring de novo missense variants located in the stem and stalk domains presented with refractory epilepsies, whereas two patients harbouring biallelic variants located in the regions between functional domains had mild epilepsy with infrequent focal seizures and favourable outcomes. One patient presented with pachygyria and neurodevelopmental abnormalities, and the other three patients presented with normal development. These variants have no or low frequencies in the Genome Aggregation Database. All the missense variants were predicted to be damaging using silico tools. Previously reported epilepsy-related variants were monoallelic variants, mainly de novo missense variants, and all the patients presented with severe epileptic phenotypes or developmental delay and malformations of cortical development. Epilepsy-related variants were clustered in the dimerization and stalk domains, and generalized epilepsy-associated variants were distributed in the stem domain.
CONCLUSION
This study suggested that DYNC1H1 variants are potentially associated with infant-onset epilepsy without neurodevelopmental disorders, expanding the phenotypic spectrum of DYNC1H1. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic variation.
Topics: Infant; Humans; Mutation; Epilepsy; Neurodevelopmental Disorders; Epilepsy, Generalized; Mutation, Missense; Phenotype; Cytoplasmic Dyneins
PubMed: 37903666
DOI: 10.1016/j.seizure.2023.10.010 -
Turkish Archives of Pediatrics Jul 2021The purpose of this study is to classify the malformations of cortical development in children according to the embryological formation, localization, and...
AIM
The purpose of this study is to classify the malformations of cortical development in children according to the embryological formation, localization, and neurodevelopmental findings. Seizure/epilepsy and electrophysiological findings have also been compared.
MATERIAL AND METHODS
Seventy-five children (age: 1 month-16.5 years; 56% male) followed with the diagnosis of malformation of cortical development, in Marmara University Pendik Research and Educational Hospital Department of Pediatric Neurology, were included in the study. Their epilepsy characteristics, electroencephalogram (EEG) findings, and prognosis were reported. Neurodevelopmental characteristics were evaluated by the Bayley Scales of Infant and Toddler Development (Bayley-III) for the ages of 0-42 months ( = 30); the Denver Developmental Screening Test-II (DDST-II) for ages 42 months-6 years ( = 11); and the Wechsler Intelligence Scales for Children (WISC-R), used for children 6 years and older ( = 34).
RESULTS
The patients were classified as 44% premigrational (14.6% microcephaly, 24% tuberous sclerosis, 2.7% focal cortical dysplasia, 1.3% hemimegalencephaly, and 1.3% diffuse cortical dysgenesis); 17.3% migrational (14.6% lissencephaly, 2.7% heterotopia); and 38.6% postmigrational (14.6% schizencephaly, 24% polymicrogyria) developmentally. According to involved area, the classification was 34.7% hemispheric/multilobar, 33.3% diffuse, and 32% focal. Seventy-five percent of the patients had a history of epilepsy, and 92% were resistant to treatment. The seizures started before the age of 12 months in diffuse malformations, and epileptic encephalopathy was more common in microcephaly with a rate of 80% and lissencephaly with a rate of 54.5% in the first EEGs. Ninety-five percent of patients had at least one level of neurodevelopmental delay detected by DDST/Bayley-III; this was more common in patients with accompanying epilepsy ( < .05). As seen more commonly in patients with diffuse pathologies and intractable frequent seizures, mental retardation was detected by WISC-R in 64.5% of patients ( < .05).
CONCLUSION
In cases with cortical developmental malformation, epilepsy/EEG features and neurodevelopmental prognosis can be predicted depending on the developmental process and type and extent of involvement. Patients should be followed up closely with EEG.
PubMed: 35005731
DOI: 10.5152/TurkArchPediatr.2021.20148 -
Neurology India 2023Incomplete hippocampal inversion (IHI) is a developmental failure of normal hippocampal inversion. Previous studies have described IHI in epilepsy and non-epilepsy...
BACKGROUND AND PURPOSE
Incomplete hippocampal inversion (IHI) is a developmental failure of normal hippocampal inversion. Previous studies have described IHI in epilepsy and non-epilepsy subjects. IHI has also been reported with malformations of cortical development (MCDs) and corpus callosal agenesis that have association with neuropsychiatric disorders such as autism spectrum disorder (ASD). This study aims to describe the clinical profile of magnetic resonance imaging (MRI)-diagnosed IHI.
MATERIALS AND METHODS
We studied patients with IHI who were identified after a retrospective review of the MRI archives of the past 3 years. The MRI findings of partial and total IHI were included. The clinical profiles associated with IHI were classified into epilepsy and non-epilepsy categories.
RESULTS
A retrospective review of MRI done over 3 years revealed 54 cases of IHI (32 left-sided, 20 bilateral, and 2 isolated right-sided), and out of 74 IHI, 59 were of total type and 15 partial. Thirty-six subjects (61.1%) had epilepsy (9 with neurodevelopmental problems), 17 subjects (31.5%) had ASD, and 4 subjects (7.4%) had only neurodevelopmental disorders. MCDs were seen in 7 (12.9%): polymicrogyria (4), periventricular heterotopia (2), and pachygyria (1). Hippocampal volume loss was seen in 10, and contralateral mesial temporal sclerosis was seen in 2 patients.
CONCLUSION
Hippocampal inversion has been reported in MRI scans of patients with epilepsy, ASD, MCDs, and many other related disorders. Further studies are required to know its occurrence among patients who get MRI scans due to many other disorders such as headaches, psychiatric disorders, minor hear trauma, and perinatal insults. If possible, studies among normal populations also need to be done.
Topics: Humans; Autism Spectrum Disorder; Hippocampus; Epilepsy; Magnetic Resonance Imaging; Neuroimaging
PubMed: 38174460
DOI: 10.4103/0028-3886.391380 -
Journal of Neural Transmission (Vienna,... Nov 2022Symptoms of obsessive-compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive-compulsive symptoms (OCS)...
Symptoms of obsessive-compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive-compulsive symptoms (OCS) and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C > T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology.
Topics: Abnormalities, Multiple; Actins; Adult; Craniofacial Abnormalities; Epilepsy; Facies; Hemosiderin; Humans; Intellectual Disability; Lissencephaly; Male; Obsessive-Compulsive Disorder
PubMed: 36205783
DOI: 10.1007/s00702-022-02544-y -
Clinical Genetics Sep 2020Biallelic loss-of-function mutations in the centrosomal pericentrin gene (PCNT) cause microcephalic osteodysplastic primordial dwarfism type II (MOPDII), which is...
Biallelic loss-of-function mutations in the centrosomal pericentrin gene (PCNT) cause microcephalic osteodysplastic primordial dwarfism type II (MOPDII), which is characterized by extreme growth retardation, microcephaly, skeletal dysplasia, and dental anomalies. Life expectancy is reduced due to a high risk of cerebral vascular anomalies. Here, we report two siblings with MOPDII and attenuated growth restriction, and pachygyria. Compound heterozygosity for two novel truncated PCNT variants was identified. Both truncated PCNT proteins were expressed in patient's fibroblasts, with a reduced total protein amount compared to control. Patient's fibroblasts showed impaired cell cycle progression. As a novel finding, 20% of patient's fibroblasts were shown to express PCNT comparable to control. This was associated with normal mitotic morphology and normal co-localization of mutated PCNT with centrosome-associated proteins γ-tubulin and centrin 3, suggesting some residual function of truncated PCNT proteins. These data expand the clinical and molecular spectrum of MOPDII and indicate that residual PCNT function might be associated with attenuated growth restriction in MOPDII.
Topics: Adolescent; Adult; Alleles; Antigens; Centrosome; Child; Child, Preschool; Dwarfism; Female; Fetal Growth Retardation; Fibroblasts; Genetic Predisposition to Disease; Humans; Lissencephaly; Loss of Function Mutation; Male; Microcephaly; Osteochondrodysplasias; Siblings; Tubulin; Young Adult
PubMed: 32557621
DOI: 10.1111/cge.13797