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The Neuroscientist : a Review Journal... Aug 2023The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and... (Review)
Review
The cerebral cortex develops through a carefully conscripted series of cellular and molecular events that culminate in the production of highly specialized neuronal and glial cells. During development, cortical neurons and glia acquire a precise cellular arrangement and architecture to support higher-order cognitive functioning. Decades of study using rodent models, naturally gyrencephalic animal models, human pathology specimens, and, recently, human cerebral organoids, reveal that rodents recapitulate some but not all the cellular and molecular features of human cortices. Whereas rodent cortices are smooth-surfaced or lissencephalic, larger mammals, including humans and nonhuman primates, have highly folded/gyrencephalic cortices that accommodate an expansion in neuronal mass and increase in surface area. Several genes have evolved to drive cortical gyrification, arising from gene duplications or de novo origins, or by alterations to the structure/function of ancestral genes or their gene regulatory regions. Primary cortical folds arise in stereotypical locations, prefigured by a molecular "blueprint" that is set up by several signaling pathways (e.g., Notch, Fgf, Wnt, PI3K, Shh) and influenced by the extracellular matrix. Mutations that affect neural progenitor cell proliferation and/or neurogenesis, predominantly of upper-layer neurons, perturb cortical gyrification. Below we review the molecular drivers of cortical folding and their roles in disease.
PubMed: 37621149
DOI: 10.1177/10738584231190839 -
Acta Veterinaria Scandinavica Jun 2020Lissencephaly is a brain malformation characterized by smooth and thickened cerebral surface, which may result in structural epilepsy. Lissencephaly is not common in...
BACKGROUND
Lissencephaly is a brain malformation characterized by smooth and thickened cerebral surface, which may result in structural epilepsy. Lissencephaly is not common in veterinary medicine. Here, we characterize the first cases of lissencephaly in four Shih Tzu dogs, including clinical presentations and findings of magnetic resonance imaging of lissencephaly and several concomitant brain malformations.
CASE PRESENTATION
Early-onset acute signs of forebrain abnormalities were observed in all dogs, which were mainly cluster seizures and behavioral alterations. Based on neurological examination, the findings were consistent with symmetrical and bilateral forebrain lesions. Metabolic disorders and inflammatory diseases were excluded. Magnetic resonance imaging for three dogs showed diffuse neocortical agyria and thickened gray matter while one dog had mixed agyria and pachygyria. Other features, such as internal hydrocephalus, supracollicular fluid accumulation, and corpus callosum hypoplasia, were detected concomitantly. Antiepileptic drugs effectively controlled cluster seizures, however, sporadic isolated seizures and signs of forebrain abnormalities, such as behavioral alterations, central blindness, and strabismus persisted.
CONCLUSIONS
Lissencephaly should be considered an important differential diagnosis in Shih Tzu dogs presenting with early-onset signs of forebrain abnormalities, including cluster seizures and behavioral alterations. Magnetic resonance imaging was appropriate for ante-mortem diagnosis of lissencephaly and associated cerebral anomalies.
Topics: Animals; Anticonvulsants; Dog Diseases; Dogs; Epilepsy; Female; Lissencephaly; Magnetic Resonance Imaging; Male
PubMed: 32563254
DOI: 10.1186/s13028-020-00528-0 -
Seminars in Pediatric Neurology Sep 2009Genetic microcephaly and lissencephaly are 2 of the most common brain malformations. Each of them is a heterogeneous group of disorders caused by mutations of many... (Review)
Review
Genetic microcephaly and lissencephaly are 2 of the most common brain malformations. Each of them is a heterogeneous group of disorders caused by mutations of many different genes. They are a significant cause of neurological morbidity in children worldwide, responsible for many cases of mental retardation, cerebral palsy, and epilepsy. Recent advances in molecular genetics have led to the identification of several genes causing these disorders, and thus accurate molecular diagnosis and improved genetic counseling has become available for many patients and their families. More recently identified genes include STIL, causing primary autosomal recessive microcephaly (microcephaly vera), and TUBA1A, causing lissencephaly. Numerous other disease genes are likely still to be identified. Functional studies of genes that cause microcephaly and lissencephaly have provided valuable insight into the molecular mechanisms of human brain development.
Topics: Animals; Humans; Lissencephaly; Magnetic Resonance Imaging; Microcephaly
PubMed: 19778709
DOI: 10.1016/j.spen.2009.07.001 -
American Journal of Medical Genetics.... Feb 2023Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker... (Review)
Review
Deletion of 17p13.3 has varying degrees of severity on brain development based on precise location and size of the deletion. The most severe phenotype is Miller-Dieker syndrome (MDS) which is characterized by lissencephaly, dysmorphic facial features, growth failure, developmental disability, and often early death. Haploinsufficiency of PAFAH1B1 is responsible for the characteristic lissencephaly in MDS. The precise role of YWHAE haploinsufficiency in MDS is unclear. Case reports are beginning to elucidate the phenotypes of individuals with 17p13.3 deletions that have deletion of YWHAE but do not include deletion of PAFAH1B1. Through our clinical genetics practice, we identified four individuals with 17p13.3 deletion that include YWHAE but not PAFAH1B1. These patients have a similar phenotype of dysmorphic facial features, developmental delay, and leukoencephalopathy. In a review of the literature, we identified 19 patients with 17p13.3 microdeletion sparing PAFAH1B1 but deleting YWHAE. Haploinsufficiency of YWHAE is associated with brain abnormalities including cystic changes. These individuals have high frequency of epilepsy, intellectual disability, and dysmorphic facial features including prominent forehead, epicanthal folds, and broad nasal root. We conclude that deletion of 17p13.3 excluding PAFAH1B1 but including YWHAE is associated with a consistent phenotype and should be considered a distinct condition from MDS.
Topics: Humans; Classical Lissencephalies and Subcortical Band Heterotopias; Chromosome Deletion; Lissencephaly; Phenotype; Intellectual Disability; Chromosomes, Human, Pair 17; Brain; 14-3-3 Proteins
PubMed: 36433683
DOI: 10.1002/ajmg.a.63057 -
Nature Communications May 2022Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter....
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
Topics: Animals; Cell Movement; Cerebral Cortex; Classical Lissencephalies and Subcortical Band Heterotopias; Humans; Mice; Mice, Knockout; Neurogenesis; Neurons; SAP90-PSD95 Associated Proteins
PubMed: 35585091
DOI: 10.1038/s41467-022-30443-z -
American Journal of Medical Genetics.... Jun 2017Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral...
Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS-LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adolescent; Adult; Cerebral Cortex; Child; Child, Preschool; Classical Lissencephalies and Subcortical Band Heterotopias; Doublecortin Domain Proteins; Doublecortin Protein; Female; Humans; Infant; Infant, Newborn; Lissencephaly; Magnetic Resonance Imaging; Male; Microtubule-Associated Proteins; Mutation; Neuropeptides; Phenotype; Young Adult
PubMed: 28440899
DOI: 10.1002/ajmg.a.38245 -
Orphanet Journal of Rare Diseases Feb 2019The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical... (Review)
Review
BACKGROUND
The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.
RESULTS
In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G > A, p.(Gly436Asp) variant was novel, the two variants c.518C > T, p.(Pro173Leu) and c.641G > A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (agyria-pachygyria) (70%), although reporting was incomplete in the different studies. We identified a total of 121 specific variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein model, 38.6% of all disease-causing variants including those in the C-terminal region are predicted to affect the binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.
CONCLUSIONS
With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.
Topics: Adolescent; Child; Corpus Callosum; Female; Genotype; Humans; Lissencephaly; Male; Microcephaly; Mutation, Missense; Phenotype; Tubulin
PubMed: 30744660
DOI: 10.1186/s13023-019-1020-x -
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 -
Nature Structural & Molecular Biology Sep 2023Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active...
Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly. Lis1 is required for active dynein complexes to form, but how it enables this is unclear. Here, we present a structure of two yeast dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed 'Chi,' are required for Lis1's regulation of dynein in Saccharomyces cerevisiae in vivo and the formation of active human dynein-dynactin-activating adapter complexes in vitro. We propose that this structure represents an intermediate in dynein's activation pathway, revealing how Lis1 relieves dynein's autoinhibited state.
Topics: Animals; Humans; Cytoplasmic Dyneins; Dyneins; Classical Lissencephalies and Subcortical Band Heterotopias; Biological Transport; Cytoskeleton; Dynactin Complex; Oligonucleotides; Mammals
PubMed: 37620585
DOI: 10.1038/s41594-023-01069-6 -
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