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Cells Dec 2019Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which... (Review)
Review
Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.
Topics: Cell Proliferation; Chromosome Segregation; Humans; Kinetochores; Microcephaly; Mitosis; Neurodevelopmental Disorders; Spindle Apparatus
PubMed: 31878213
DOI: 10.3390/cells9010049 -
ELife Jun 2023WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions. Recessive mutations in cause structural brain abnormalities and account for the second...
WDR62 is a spindle pole-associated scaffold protein with pleiotropic functions. Recessive mutations in cause structural brain abnormalities and account for the second most common cause of autosomal recessive primary microcephaly (MCPH), indicating WDR62 as a critical hub for human brain development. Here, we investigated WDR62 function in corticogenesis through the analysis of a C-terminal truncating mutation (D955AfsX112). Using induced Pluripotent Stem Cells (iPSCs) obtained from a patient and his unaffected parent, as well as isogenic corrected lines, we generated 2D and 3D models of human neurodevelopment, including neuroepithelial stem cells, cerebro-cortical progenitors, terminally differentiated neurons, and cerebral organoids. We report that WDR62 localizes to the Golgi apparatus during interphase in cultured cells and human fetal brain tissue, and translocates to the mitotic spindle poles in a microtubule-dependent manner. Moreover, we demonstrate that WDR62 dysfunction impairs mitotic progression and results in alterations of the neurogenic trajectories of iPSC neuroderivatives. In summary, impairment of WDR62 localization and function results in severe neurodevelopmental abnormalities, thus delineating new mechanisms in the etiology of MCPH.
Topics: Golgi Apparatus; Spindle Poles; Humans; Microcephaly; Nerve Tissue Proteins; Cell Cycle Proteins; Male; Induced Pluripotent Stem Cells; Mitosis; Child; Adolescent
PubMed: 37272619
DOI: 10.7554/eLife.81716 -
Journal of Paediatrics and Child Health Mar 2022To describe clinical characteristics, outcomes and causes of microcephaly in children whose condition was identified within the first year of life.
AIM
To describe clinical characteristics, outcomes and causes of microcephaly in children whose condition was identified within the first year of life.
METHODS
Retrospective review of medical records of microcephalic children born between 2008 and 2018 and admitted for any reason during the same period to a tertiary paediatric hospital. Microcephaly was defined as occipitofrontal circumference (OFC) more than two standard deviations below the mean (>-2 SD).
RESULTS
Between January 2008 and September 2018, 1083 medical records were retrieved. Of the children, 886 were ineligible and 197 were confirmed cases of microcephaly. Of cases, 73 (37%) had primary microcephaly (at birth) and 72 (37%) had severe microcephaly (OFC > -3 SD). Of microcephalic children, 192 (98%) had congenital anomalies, of whom 93% had major anomalies, mostly cardiovascular or musculoskeletal. Neurological signs or symptoms were reported in 148 (75%), seizures being the most common. Of the 139 children with abnormal central nervous system (CNS) imaging, one or more structural brain abnormalities were identified in 124 (89%). Failure to reach developmental milestones was observed in 69%, visual impairment in 41% and cerebral palsy in 13%. Microcephaly was idiopathic in 51% and 24% had diagnosed genetic disorders. There was no association between developmental outcomes or structural brain anomalies and severity of microcephaly or timing of diagnosis.
CONCLUSION
Our results suggest the need for a systematic investigative approach to diagnosis, including a careful history, examination, genetic testing and neuroimaging, to determine the underlying cause of microcephaly, identify co-morbidities, predict prognosis and guide genetic counselling and therapy.
Topics: Australia; Child; Humans; Infant; Infant, Newborn; Microcephaly; Nervous System Malformations; Neuroimaging; Retrospective Studies
PubMed: 34553803
DOI: 10.1111/jpc.15739 -
Brain : a Journal of Neurology Aug 2023Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes...
Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of loss-of-function SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal nuclear envelope breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the nuclear envelope. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions. We hypothesize that, in individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4 and interferes with cerebral corticogenesis and survival of pancreatic beta cells.
Topics: Humans; Animals; Mice; Nuclear Envelope; Microcephaly; Sphingomyelin Phosphodiesterase; Nuclear Pore; Mitosis; Diabetes Mellitus
PubMed: 36732302
DOI: 10.1093/brain/awad033 -
Genes Aug 2023-related disorders are a form of rare X-linked neurological diseases and most of the patients are females. They are characterized by several symptoms, including... (Review)
Review
-related disorders are a form of rare X-linked neurological diseases and most of the patients are females. They are characterized by several symptoms, including microcephaly with pontine and cerebellar hypoplasia (MICPCH), epilepsy, congenital nystagmus, and neurodevelopmental disorders. Whole-genome sequencing has identified various mutations, including nonsense and missense mutations, from patients with -related disorders, revealing correlations between specific mutations and clinical phenotypes. Notably, missense mutations associated with epilepsy and intellectual disability were found throughout the whole region of the CASK protein, while missense mutations related to microcephaly and MICPCH were restricted in certain domains. To investigate the pathophysiology of -related disorders, research groups have employed diverse methods, including the generation of knockout mice and the supplementation of CASK to rescue the phenotypes. These approaches have yielded valuable insights into the identification of functional domains of the CASK protein associated with a specific phenotype. Additionally, recent advancements in the AI-based prediction of protein structure, such as AlphaFold2, and the application of genome-editing techniques to generate mutant mice carrying missense mutations from patients with -related disorders, allow us to understand the pathophysiology of -related disorders in more depth and to develop novel therapeutic methods for the fundamental treatment of -related disorders.
Topics: Female; Animals; Mice; Male; Microcephaly; Mutation; Mice, Knockout; Phenotype; Rare Diseases
PubMed: 37628707
DOI: 10.3390/genes14081656 -
Disease Models & Mechanisms Jul 2023An outbreak of births of microcephalic patients in Brazil motivated multiple studies on this incident. The data left no doubt that infection by Zika virus (ZIKV) was the... (Review)
Review
An outbreak of births of microcephalic patients in Brazil motivated multiple studies on this incident. The data left no doubt that infection by Zika virus (ZIKV) was the cause, and that this virus promotes reduction in neuron numbers and neuronal death. Analysis of patients' characteristics revealed additional aspects of the pathology alongside the decrease in neuronal number. Here, we review the data from human, molecular, cell and animal model studies attempting to build the natural history of ZIKV in the embryonic central nervous system (CNS). We discuss how identifying the timing of infection and the pathways through which ZIKV may infect and spread through the CNS can help explain the diversity of phenotypes found in congenital ZIKV syndrome (CZVS). We suggest that intraneuronal viral transport is the primary mechanism of ZIKV spread in the embryonic brain and is responsible for most cases of CZVS. According to this hypothesis, the viral transport through the blood-brain barrier and cerebrospinal fluid is responsible for more severe pathologies in which ZIKV-induced malformations occur along the entire anteroposterior CNS axis.
Topics: Animals; Humans; Zika Virus; Zika Virus Infection; Microcephaly; Central Nervous System; Blood-Brain Barrier; Brain
PubMed: 37458166
DOI: 10.1242/dmm.050005 -
International Journal of Biological... 2023Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome,...
Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of , a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mechanisms underlying microcephaly, we developed Nibp/Trappc9-deficient animal models using different techniques, including morpholino knockdown and CRISPR/Cas mutation in zebrafish and Cre/LoxP-mediated gene targeting in mice. Nibp/Trappc9 deficiency impaired the stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones. This deficiency also impaired elongation and branching of neuronal dendrites and axons, without significant effects on neurite initiation or neural cell number/types in embryonic and adult brains. The positive correlation of TRAPPII stability and neurite elongation/branching suggests a potential role for TRAPPII in regulating neurite morphology. These results provide novel genetic/molecular evidence to define patients with a type of non-syndromic autosomal recessive intellectual disability and highlight the importance of developing therapeutic approaches targeting the TRAPPII complex to cure TRAPPopathies.
Topics: Animals; Mice; Intellectual Disability; Microcephaly; Neurites; Neurons; Zebrafish
PubMed: 37416774
DOI: 10.7150/ijbs.78489 -
Revista de Saude Publica 2022To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with...
OBJECTIVE
To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with microcephaly via data mining.
METHODS
In autopsy studies, head circumference was measured with an inelastic tape placed around the skull. Total brain volume was also directly measured. A linear regression was used to determine the association of head circumference with brain volume and clinical variables. Microcephaly was defined as head circumference that were two standard deviations below the mean of significant clinical variables. We further applied an association rule mining to find rules associating microcephaly with several sociodemographic and clinical variables.
RESULTS
In our sample of 2,508 adults, the mean head circumference was 55.3 ± 2.7cm. Head circumference was related to height, cerebral volume, and sex (p < 0.001 for all). Microcephaly was present in 4.7% of the sample (n = 119). Out of 34,355 association rules, we found significant relationships between microcephaly and a clinical dementia rating (CDR) > 0.5 with an informant questionnaire on cognitive decline in the elderly (IQCODE) ≥ 3.4 (confidence: 100% and lift: 5.6), between microcephaly and a CDR > 0.5 with age over 70 years (confidence: 42% and lift: 2.4), and microcephaly and males (confidence: 68.1% and lift: 1.3).
CONCLUSION
Head circumference was related to cerebral volume. Due to its low cost and easy use, head circumference can be used as a screening test for microcephaly, adjusting it for gender and height. Microcephaly was associated with dementia at old age.
Topics: Adult; Aged; Brain; Brazil; Cephalometry; Head; Humans; Male; Microcephaly
PubMed: 35649085
DOI: 10.11606/s1518-8787.2022056004175 -
European Journal of Medical Genetics Dec 2022Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary...
Pathogenic variants in CENPJ have been first identified in consanguineous Pakistani families with Hereditary Primary Microcephaly type 6 (MCPH6). In addition to primary microcephaly, the CENPJ-related phenotypic spectrum lately included also distinctive and peculiar 'bird-like' craniofacial dysmorphisms, intrauterine and/or postnatal growth retardation, and moderate to severe intellectual disability (ID). These features are also part of the clinical spectrum of Seckel syndrome (SCKL) a genetically heterogeneous neurodevelopmental condition caused by mutations in different genes involved in cell cycle progression. Among these, CENPJ is responsible for type 4 Seckel syndrome (SCKL4). The literature reports two individuals affected by SCKL4 suffering from seizures and other two individuals with other brain malformations in addition to microcephaly. However, neither epilepsy nor brain malformations are described in detail and genotype-phenotype information remains limited. We describe the first Caucasian affected with SCKL4 and harboring a novel, homozygous mutation in CENPJ. We detail the clinical and neuroradiological findings including structural focal epilepsy and a severe brain malformation (i.e., hydranencephaly) that was never associated with SCKL4 to date.
Topics: Humans; Microcephaly; Hydranencephaly; Dwarfism; Facies; Intellectual Disability; Mutation; Microtubule-Associated Proteins
PubMed: 36334884
DOI: 10.1016/j.ejmg.2022.104659 -
Molecular Biology Reports Apr 2020Zika virus is a mosquito-borne Flavivirus originally isolated from humans in 1952. Following its re-emergence in Brazil in 2015, an increase in the number of babies born... (Review)
Review
Zika virus is a mosquito-borne Flavivirus originally isolated from humans in 1952. Following its re-emergence in Brazil in 2015, an increase in the number of babies born with microcephaly to infected mothers was observed. Microcephaly is a neurodevelopmental disorder, characterised phenotypically by a smaller than average head size, and is usually developed in utero. The 2015 outbreak in the Americas led to the World Health Organisation declaring Zika a Public Health Emergency of International Concern. Since then, much research into the effects of Zika has been carried out. Studies have investigated the structure of the virus, its effects on and evasion of the immune response, cellular entry including target receptors, its transmission from infected mother to foetus and its cellular targets. This review discusses current knowledge and novel research into these areas, in hope of developing a further understanding of how exposure of pregnant women to the Zika virus can lead to impaired brain development of their foetus. Although no longer considered an epidemic in the Americas, the mechanism by which Zika acts is still not comprehensively and wholly understood, and this understanding will be crucial in developing effective vaccines and treatments.
Topics: Brain; Brazil; Disease Outbreaks; Female; Humans; Infant; Microcephaly; Pregnancy; Public Health; Zika Virus; Zika Virus Infection
PubMed: 32128708
DOI: 10.1007/s11033-020-05349-y