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

ABSTRACT: 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.

SUBMITTER: Markus F

PROVIDER: S-EPMC8612930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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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.

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Combinations of deletion and missense variations of the dynein-2 DYNC2LI1 subunit found in skeletal ciliopathies cause ciliary defects.

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