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A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat.

ABSTRACT: Children with malformations of cortical development (MCD) are at risk for epilepsy, developmental delays, behavioral disorders, and intellectual disabilities. For a subset of these children, antiseizure medications or epilepsy surgery may result in seizure freedom. However, there are limited options for treating or curing the other conditions, and epilepsy surgery is not an option in all cases of pharmacoresistant epilepsy. Understanding the genetic and neurobiological mechanisms underlying MCD is a necessary step in elucidating novel therapeutic targets. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD with spontaneous seizures, but the underlying genetic mutation(s) have remained unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated first exon markedly diminished Eml1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat revealed early-onset of spontaneous spike-wave discharge (SWD) bursts beginning at postnatal day (P) 17. A dihybrid cross demonstrated that the mutant Eml1 allele segregates with the observed dysplastic cortex and the early-onset SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a deletion in Eml1.

SUBMITTER: Grosenbaugh DK

PROVIDER: S-EPMC7814471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat

Project description:Malformations of cortical development (MCD) are present in up to 40% of children with pharmacoresistant epilepsy. Although epilepsy surgery can be successful in a subset of children, not all forms of MCD are operable. Understanding the genetic and neurobiological mechanisms underlying MCD and MCD-related epilepsy are necessary for the development of novel anti-epilepsy drugs. The tish (telencephalic internal structural heterotopia) rat is a unique model of MCD and spontaneous seizures, but the underlying genetic mutation has been, heretofore, unknown. DNA and RNA-sequencing revealed that a deletion encompassing a previously unannotated exon markedly diminished EML1 transcript and protein abundance in the tish brain. Developmental electrographic characterization of the tish rat demonstrated spontaneous spike-wave discharge (SWD) bursts beginning as early as postnatal day (P) 17. A dihybrid cross demonstrated that the mutantEml1 allele segregates with the observed dysplastic cortex and SWD bursts in monogenic autosomal recessive frequencies. Our data link the development of the bilateral, heterotopic dysplastic cortex of the tish rat to a mutation in Eml1 and provide a novel rat model of MCD.

2020-03-28 | GSE147663 | GEO

A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat

Project description:A deletion in Eml1 leads to bilateral subcortical heterotopia in the tish rat

| PRJNA615896 | ENA

A novel missense variant in the EML1 gene associated with bilateral ribbon-like subcortical heterotopia leads to ciliary defects.

Project description:Heterotopia is a brain malformation caused by a failed migration of cortical neurons during development. Clinical symptoms of heterotopia vary in severity of intellectual disability and may be associated with epileptic disorders. Abnormal neuronal migration is known to be associated with mutations in the doublecortin gene (DCX), the platelet-activating factor acetylhydrolase gene (PAFAH1B1), or tubulin alpha-1A gene (TUBA1A). Recently, a new gene encoding echinoderm microtubule-associated protein-like 1 (EML1) was reported to cause a particular form of subcortical heterotopia, the ribbon-like subcortical heterotopia (RSH). EML1 mutations are inherited in an autosomal recessive manner. Only six unrelated EML1-associated heterotopia-affected families were reported so far. The EML1 protein is a member of the microtubule-associated proteins family, playing an important role in microtubule assembly and stabilization as well as in mitotic spindle formation in interphase. Herein, we present a novel homozygous missense variant in EML1 (NM_004434.2: c.692G>A, NP_004425.2: p.Gly231Asp) identified in a male RSH-affected patient. Our clinical and molecular findings confirm the genotype-phenotype associations of EML1 mutations and RSH. Analyses of patient-derived fibroblasts showed the significantly reduced length of primary cilia. In addition, our results presented, that the mutated EML1 protein did not change binding capacities with tubulin. The data described herein will expand the mutation spectrum of the EML1 gene and provide further insight into molecular and cellular bases of the pathogenic mechanisms underlying RSH.

| S-EPMC8612930 | biostudies-literature

Forebrain Eml1 depletion reveals early centrosomal dysfunction causing subcortical heterotopia

Project description:The layered structure of the cerebral cortex is formed through a complicated sequence of highly controlled stages during corticogenesis. The perturbation of neuronal migration and cell division during this process can result a rare disorder called as cortical heterotopia. EML1 is a heterotopia associated gene where the perturbations cause heterotopia formation in human as well as in mouse. To elaborate on the EML1 interactome and its disruptions by heterotopia-associated mutation, we performed BioID proximity labeling of EML1 and EML1*T243A, a human SH-associated mutant form of the protein.

2024-08-26 | PXD045846 | Pride

Bilateral subcortical heterotopia with partial callosal agenesis in a mouse mutant.

Project description:Cognition and behavior depend on the precise placement and interconnection of complex ensembles of neurons in cerebral cortex. Mutations that disrupt migration of immature neurons from the ventricular zone to the cortical plate have provided major insight into mechanisms of brain development and disease. We have discovered a new and highly penetrant spontaneous mutation that leads to large nodular bilateral subcortical heterotopias with partial callosal agenesis. The mutant phenotype was first detected in a colony of fully inbred BXD29 mice already known to harbor a mutation in Tlr4. Neurons confined to the heterotopias are mainly born in midgestation to late gestation and would normally have migrated into layers 2-4 of overlying neocortex. Callosal cross-sectional area and fiber number are reduced up to 50% compared with coisogenic wildtype BXD29 substrain controls. Mutants have a pronounced and highly selective defect in rapid auditory processing. The segregation pattern of the mutant phenotype is most consistent with a two-locus autosomal recessive model, and selective genotyping definitively rules out the Tlr4 mutation as a cause. The discovery of a novel mutation with strong pleiotropic anatomical and behavioral effects provides an important new resource for dissecting molecular mechanisms and functional consequences of errors of neuronal migration.

| S-EPMC3593577 | biostudies-literature

EML1-associated brain overgrowth syndrome with ribbon-like heterotopia.

Project description:EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment.

| S-EPMC6916563 | biostudies-literature

X-linked Bilateral Periventricular Nodular Heterotopia.

Project description:Teaching Point: Postmortem magnetic resonance imaging can replace conventional autopsy and help diagnosis in combination with other postmortem investigations (e.g. microscopic examination of the placenta, genetic testing, etc.) under the umbrella of minimal invasive autopsy.

| S-EPMC7207253 | biostudies-literature

Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay.

Project description:Lissencephaly is a severe brain malformation in which failure of neuronal migration results in agyria or pachygyria and in which the brain surface appears unusually smooth. It is often associated with microcephaly, profound intellectual disability, epilepsy, and impaired motor abilities. Twenty-two genes are associated with lissencephaly, accounting for approximately 80% of disease. Here we report on 12 individuals with a unique form of lissencephaly; these individuals come from eight unrelated families and have bi-allelic mutations in APC2, encoding adenomatous polyposis coli protein 2. Brain imaging studies demonstrate extensive posterior predominant lissencephaly, similar to PAFAH1B1-associated lissencephaly, as well as co-occurrence of subcortical heterotopia posterior to the caudate nuclei, "ribbon-like" heterotopia in the posterior frontal region, and dysplastic in-folding of the mesial occipital cortex. The established role of APC2 in integrating the actin and microtubule cytoskeletons to mediate cellular morphological changes suggests shared function with other lissencephaly-encoded cytoskeletal proteins such as ?-N-catenin (CTNNA2) and platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1, also known as LIS1). Our findings identify APC2 as a radiographically distinguishable recessive form of lissencephaly.

| S-EPMC6817548 | biostudies-literature

Familial bilateral periventricular nodular heterotopia mimics tuberous sclerosis.

Project description:A mother and daughter with an initial diagnosis of tuberous sclerosis are described. The daughter presented with partial seizures at the age of 8 months. Computed tomography showed uncalcified periventricular nodules which on magnetic resonance imaging were ovoid, almost contiguous, of grey matter density, and did not enhance with gadolinium. Brain imaging of her asymptomatic mother was similar. Absence of severe mental retardation, extracranial hamartomas, and depigmented patches distinguishes familial bilateral periventricular nodular heterotopia (FNH) from tuberous sclerosis. FNH is probably inherited as an X linked dominant with lethality in males.

| S-EPMC1511435 | biostudies-other

Periventricular nodular heterotopia in 22q11.2 deletion and frontal lobe migration.

Project description:ObjectiveWe aimed to delineate the distribution of periventricular nodular heterotopia (PNH) in patients with 22q11.2 microdeletion syndrome (22q11.2DS) and place this in the context of other genetic forms of PNH.MethodsWe retrospectively analyzed brain imaging and postmortem data available for adult patients with 22q11.2DS. We included only those with good quality MRI data (n = 29) in addition to two patients with PNH identified through postmortem studies. We also reviewed the pattern of PNH in all genetic conditions reported with this phenotype.ResultsOf the total seven patients (M = 4, F = 3; age: 19-61 years) identified to have PNH, six had a history of seizures, six had schizophrenia, six had variable levels of intellectual disability, and two had obsessive compulsive disorder. In all seven patients, the nodules were located over the dorsal pole of the frontal horn of the lateral ventricles. The nodules were small, noncontiguous, and ranged in number from 1 to 10 per individual. Our review identified 37 genetic conditions associated with PNH. With the cases reported here, 22q11.2DS becomes the fifth most commonly reported genetic condition, and the third most common copy number variation, associated with PNH.InterpretationThe neuropsychiatric manifestations in our patients with PNH support other data indicating abnormal neurodevelopment as part of the pathogenesis of 22q11.2DS.The location and cellular characteristics of PNH in 22q11.2DS overlaps with a group of migrating postnatal interneurons termed Arc cells, although more research is needed to confirm that PNH in 22q11.2DS represents Arc cells arrested in their migratory pathway.

| S-EPMC6243376 | biostudies-literature

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