Molecular Genetics of Microcephaly Primary Hereditary: An Overview

Siskos, Nikistratos; Stylianopoulou, Electra; Skavdis, George; Grigoriou, Maria

doi:10.3390/brainsci11050581

Cited by 25 publications

(25 citation statements)

References 172 publications

(291 reference statements)

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“…Currently (December 2021), twenty-eight MCPH-related genes have been identified and tagged sequentially as MCPH1–MCPH28 (MCPH; OMIM phenotypic series: PS251200; Siskos et al, 2021 ) ( Table 1 ). Still, more genetic loci are expected to exist given the fact that approximately 62% of western Europeans/North Americans and 25% of Indians/Pakistani families diagnosed with MCPH fail to show linkage to any of the MCPH loci ( Verloes et al, 1993 ; Kaindl et al, 2010 ; Sajid Hussain et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Autosomal Recessive Primary Microcephaly: Not Just a Small Brain

Zaqout

Kaindl

2022

Front. Cell Dev. Biol.

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Microcephaly or reduced head circumference results from a multitude of abnormal developmental processes affecting brain growth and/or leading to brain atrophy. Autosomal recessive primary microcephaly (MCPH) is the prototype of isolated primary (congenital) microcephaly, affecting predominantly the cerebral cortex. For MCPH, an accelerating number of mutated genes emerge annually, and they are involved in crucial steps of neurogenesis. In this review article, we provide a deeper look into the microcephalic MCPH brain. We explore cytoarchitecture focusing on the cerebral cortex and discuss diverse processes occurring at the level of neural progenitors, early generated and mature neurons, and glial cells. We aim to thereby give an overview of current knowledge in MCPH phenotype and normal brain growth.

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Section: Introductionmentioning

confidence: 99%

Autosomal Recessive Primary Microcephaly: Not Just a Small Brain

Zaqout

Kaindl

2022

Front. Cell Dev. Biol.

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“…Through this approach, new potential Prune_1 binders were identified. Among these, the interaction between Prune_1 and b-tubulin was proposed because of the crucial functions played by tubulins, MTs, and MAPs in neural development (47,48). Furthermore, this interaction was also confirmed by coimmunoprecipitation assays (Prune_1 protein and both band a-tubulins) in NBL inducible cell clones (SH-SY5Y) (10).…”

Section: Prune_1 Interaction With Aand B-tubulinsmentioning

confidence: 85%

Functional Genomics of PRUNE1 in Neurodevelopmental Disorders (NDDs) Tied to Medulloblastoma (MB) and Other Tumors

et al. 2021

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We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-β pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination.

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“…The human protein MSI1 binds to and is a translational activator of MCPH1 , a gene associated with MCPH which has various role in the cell cycle. In particular, it acts as G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1 [ 61 ]. Additionally MSI1 interacts with the Zika virus genome and enables viral replication [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

Dawidziuk¹,

Gambin²,

Bukowska‐Olech

et al. 2021

Genes

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Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.

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Molecular Genetics of Microcephaly Primary Hereditary: An Overview

Cited by 25 publications

References 172 publications

Autosomal Recessive Primary Microcephaly: Not Just a Small Brain

Autosomal Recessive Primary Microcephaly: Not Just a Small Brain

Functional Genomics of PRUNE1 in Neurodevelopmental Disorders (NDDs) Tied to Medulloblastoma (MB) and Other Tumors

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

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