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American Journal of Human Genetics Nov 2022Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require...
Non-centrosomal microtubules are essential cytoskeletal filaments that are important for neurite formation, axonal transport, and neuronal migration. They require stabilization by microtubule minus-end-targeting proteins including the CAMSAP family of molecules. Using exome sequencing on samples from five unrelated families, we show that bi-allelic CAMSAP1 loss-of-function variants cause a clinically recognizable, syndromic neuronal migration disorder. The cardinal clinical features of the syndrome include a characteristic craniofacial appearance, primary microcephaly, severe neurodevelopmental delay, cortical visual impairment, and seizures. The neuroradiological phenotype comprises a highly recognizable combination of classic lissencephaly with a posterior more severe than anterior gradient similar to PAFAH1B1(LIS1)-related lissencephaly and severe hypoplasia or absence of the corpus callosum; dysplasia of the basal ganglia, hippocampus, and midbrain; and cerebellar hypodysplasia, similar to the tubulinopathies, a group of monogenic tubulin-associated disorders of cortical dysgenesis. Neural cell rosette lineages derived from affected individuals displayed findings consistent with these phenotypes, including abnormal morphology, decreased cell proliferation, and neuronal differentiation. Camsap1-null mice displayed increased perinatal mortality, and RNAScope studies identified high expression levels in the brain throughout neurogenesis and in facial structures, consistent with the mouse and human neurodevelopmental and craniofacial phenotypes. Together our findings confirm a fundamental role of CAMSAP1 in neuronal migration and brain development and define bi-allelic variants as a cause of a clinically distinct neurodevelopmental disorder in humans and mice.
Topics: Humans; Animals; Mice; Lissencephaly; Alleles; Tubulin; Phenotype; Nervous System Malformations; Classical Lissencephalies and Subcortical Band Heterotopias; Mice, Knockout; Microtubule-Associated Proteins
PubMed: 36283405
DOI: 10.1016/j.ajhg.2022.09.012 -
Frontiers in Neuroscience 2015Neuronal migration disorders are human (or animal) diseases that result from a disruption in the normal movement of neurons from their original birth site to their final... (Review)
Review
Neuronal migration disorders are human (or animal) diseases that result from a disruption in the normal movement of neurons from their original birth site to their final destination during early development. As a consequence, the neurons remain somewhere along their migratory route, their location depending on the pathological mechanism and its severity. The neurons form characteristic abnormalities, which are morphologically classified into several types, such as lissencephaly, heterotopia, and cobblestone dysplasia. Polymicrogyria is classified as a group of malformations that appear secondary to post-migration development; however, recent findings of the underlying molecular mechanisms reveal overlapping processes in the neuronal migration and post-migration development stages. Mutations of many genes are involved in neuronal migration disorders, such as LIS1 and DCX in classical lissencephaly spectrum, TUBA1A in microlissencephaly with agenesis of the corpus callosum, and RELN and VLDLR in lissencephaly with cerebellar hypoplasia. ARX is of particular interest from basic and clinical perspectives because it is critically involved in tangential migration of GABAergic interneurons in the forebrain and its mutations cause a variety of phenotypes ranging from hydranencephaly or lissencephaly to early-onset epileptic encephalopathies, including Ohtahara syndrome and infantile spasms or intellectual disability with no brain malformations. The recent advances in gene and genome analysis technologies will enable the genetic basis of neuronal migration disorders to be unraveled, which, in turn, will facilitate genotype-phenotype correlations to be determined.
PubMed: 26052266
DOI: 10.3389/fnins.2015.00181 -
BMC Medical Genomics Dec 202217p13.3 microdeletions or microduplications (collectively known as copy number variants or CNVs) have been described in individuals with neurodevelopmental disorders....
BACKGROUND
17p13.3 microdeletions or microduplications (collectively known as copy number variants or CNVs) have been described in individuals with neurodevelopmental disorders. However, 17p13.3 CNVs were rarely reported in fetuses. This study aims to investigate the clinical significance of 17p13.3 CNVs with varied sizes and gene content in prenatal and postnatal samples.
METHODS
Eight cases with 17p13.3 CNVs out of 8806 samples that had been subjected to single nucleotide polymorphism array analysis were retrospectively analyzed, along with karyotyping, clinical features, and follow-up.
RESULTS
Eight cases with 17p13.3 CNVs consisted of five fetuses, one aborted embryo and two probands manifested severe congenital defects. The indications of prenatal testing varied considerably for the five fetuses, including ultrasound abnormalities (n = 3), segmental deletions indicated by non-invasive prenatal testing (n = 1), and intellectual disability in the mother of one fetus (n = 1). Of them, two and six harbored copy number gains and losses involving 17p13.3, respectively. The size of the detected 17p13.3 CNVs ranged from 576 kb to 5.7 Mb. Case 1 was diagnosed with 17p13.3 duplication syndrome, and cases 4, 6, and 7 with Miller-Dieker syndrome (MDS). Microdeletions of the 17p13.3 region in two cases (cases 5 and 8) involving YWHAE and CRK, sparing PAFAH1B1, were classified as pathogenic. Case 2 harbored a 576 kb microduplication, encompassing YWHAE and CRK but not PAFAH1B1, which was of maternal origin and considered a variant of uncertain significance. Case 3 carried one 74.2 Mb mosaic duplication of approximately 3.5 on chromosome 17p13.2q25.3, and two deletions at 17p13.3p13.2 and 17q25.3. The karyotype of case 3 was 46,XY,r(17)(p13q25). For five fetuses, only case 2 continued gestation and showed normal development at the age of 15 months; the others were subjected to termination of pregnancy.
CONCLUSION
The clinical findings of 17p13.3 microdeletions or microduplications varied among subjects, and 17p13.3 CNVs often differ in size and gene content. Microdeletions or microduplications containing the typical MDS region, as well as the microdeletions involving YWHAE and CRK, could be classified as pathogenic. The clinical significance of small duplications including YWHAE and CRK but not PAFAH1B1 remains uncertain, for which parental testing and clinical heterogeneity should be considered in genetic counseling.
Topics: Female; Humans; Infant; Pregnancy; Chromosome Deletion; Classical Lissencephalies and Subcortical Band Heterotopias; DNA Copy Number Variations; Polymorphism, Single Nucleotide; Retrospective Studies
PubMed: 36544138
DOI: 10.1186/s12920-022-01423-5 -
European Journal of Paediatric... Nov 2021Grey matter heterotopia (GMH) can cause of seizures and are associated with a wide range of neurodevelopmental disorders and syndromes. They are caused by a failure of...
Grey matter heterotopia (GMH) can cause of seizures and are associated with a wide range of neurodevelopmental disorders and syndromes. They are caused by a failure of neuronal migration during fetal development, leading to clusters of neurons that have not reached their final destination in the cerebral cortex. We have performed an extensive literature search in Pubmed, OMIM, and Google scholar and provide an overview of known genetic associations with periventricular nodular heterotopia (PNVH), subcortical band heterotopia (SBH) and other subcortical heterotopia (SUBH). We classified the heterotopias as PVNH, SBH, SUBH or other and collected the genetic information, frequency, imaging features and salient features in tables for every subtype of heterotopia. This resulted in 105 PVNH, 16 SBH and 25 SUBH gene/locus associations, making a total of 146 genes and chromosomal loci. Our study emphasizes the extreme genetic heterogeneity underlying GMH. It will aid the clinician in establishing an differential diagnosis and eventually a molecular diagnosis in GMH patients. A diagnosis enables proper counseling of prognosis and recurrence risks, and enables individualized patient management.
Topics: Cerebral Cortex; Classical Lissencephalies and Subcortical Band Heterotopias; Gray Matter; Humans; Magnetic Resonance Imaging; Periventricular Nodular Heterotopia; Seizures
PubMed: 34666232
DOI: 10.1016/j.ejpn.2021.09.015 -
Biomechanics and Modeling in... Oct 2015The human brain is the continuous subject of extensive investigation aimed at understanding its behavior and function. Despite a clear evidence that mechanical factors... (Review)
Review
The human brain is the continuous subject of extensive investigation aimed at understanding its behavior and function. Despite a clear evidence that mechanical factors play an important role in regulating brain activity, current research efforts focus mainly on the biochemical or electrophysiological activity of the brain. Here, we show that classical mechanical concepts including deformations, stretch, strain, strain rate, pressure, and stress play a crucial role in modulating both brain form and brain function. This opinion piece synthesizes expertise in applied mathematics, solid and fluid mechanics, biomechanics, experimentation, material sciences, neuropathology, and neurosurgery to address today's open questions at the forefront of neuromechanics. We critically review the current literature and discuss challenges related to neurodevelopment, cerebral edema, lissencephaly, polymicrogyria, hydrocephaly, craniectomy, spinal cord injury, tumor growth, traumatic brain injury, and shaken baby syndrome. The multi-disciplinary analysis of these various phenomena and pathologies presents new opportunities and suggests that mechanical modeling is a central tool to bridge the scales by synthesizing information from the molecular via the cellular and tissue all the way to the organ level.
Topics: Animals; Brain; Brain Diseases; Compressive Strength; Computer Simulation; Elastic Modulus; Humans; Intracranial Pressure; Mechanotransduction, Cellular; Models, Neurological; Neurons; Stress, Mechanical; Tensile Strength
PubMed: 25716305
DOI: 10.1007/s10237-015-0662-4 -
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 -
Epilepsia Sep 2012Epilepsy is a heterogeneous group of disorders, often associated with significant comorbidity, such as intellectual disability and skin disorder. The genetic... (Review)
Review
Epilepsy is a heterogeneous group of disorders, often associated with significant comorbidity, such as intellectual disability and skin disorder. The genetic underpinnings of many epilepsies are still being elucidated, and we expect further advances over the coming 5 years, as genetic technology improves and prices fall for whole exome and whole genome sequencing. At present, there are several well-characterized complex epilepsies associated with single gene disorders; we review some of these here. They include well-recognized syndromes such as tuberous sclerosis complex, epilepsy associated with Rett syndrome, some of the progressive myoclonic epilepsies, and novel disorders such as epilepsy associated with mutations in the PCDH 19 gene. These disorders are important in informing genetic testing to confirm a diagnosis and to permit better understanding of the variability in phenotype-genotype correlation.
Topics: Angelman Syndrome; Cadherins; Classical Lissencephalies and Subcortical Band Heterotopias; Epilepsy; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Humans; Lafora Disease; MERRF Syndrome; Neurofibromatoses; Protocadherins; Rett Syndrome; Tuberous Sclerosis; Unverricht-Lundborg Syndrome
PubMed: 22946725
DOI: 10.1111/j.1528-1167.2012.03617.x -
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 -
Seminars in Cell & Developmental Biology Oct 2010Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. The two most common genes mutated... (Review)
Review
Lissencephaly is a severe human neuronal migration defect characterized by a smooth cerebral surface, mental retardation and seizures. The two most common genes mutated in patients with lissencephaly are LIS1 and DCX. LIS1 was the first gene cloned that was important for neuronal migration in any organism, and heterozygous mutations or deletions of LIS1 are found in the majority of patients with lissencephaly, while DCX mutations were found in males with X-linked lissencephaly. In this review, we will discuss how an understanding of the molecular and cellular pathways disrupted in model organisms with Lis1 and Dcx mutations or knock-down not only provide insights into the normal processes of neuronal migration, including neurogenesis, but they also may lead to potential novel therapeutic strategies for these severe cortical malformations.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Classical Lissencephalies and Subcortical Band Heterotopias; Disease Models, Animal; Doublecortin Domain Proteins; Doublecortin Protein; Humans; Lissencephaly; Male; Mice; Microtubule-Associated Proteins; Neurogenesis; Neuropeptides; Rats
PubMed: 20688183
DOI: 10.1016/j.semcdb.2010.07.008 -
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