A novel missense variant in the EML1 gene associated with bilateral ribbon-like subcortical heterotopia leads to ciliary defects
| Autor: | Annika Kannengießer, Patricia Näder, Marta Owczarek-Lipska, Paul Atigbire, Christine Vössing, Fenja Markus, G. Christoph Korenke, Eva Bültmann, John Neidhardt, Alexander Scholten |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Models Molecular Protein Conformation DNA Mutational Analysis Mutation Missense medicine.disease_cause Article 03 medical and health sciences PAFAH1B1 Consanguinity Structure-Activity Relationship 0302 clinical medicine Exome Sequencing Genetics medicine Missense mutation Humans Genetic Predisposition to Disease Cilia Child Gene Genetics (clinical) Alleles Genetic Association Studies Mutation biology Cilium Homozygote Neurodevelopmental disorders Brain Fibroblasts medicine.disease Doublecortin Pedigree Malformations of Cortical Development 030104 developmental biology Heterotopia (medicine) Tubulin Phenotype biology.protein Microtubule-Associated Proteins 030217 neurology & neurosurgery |
| Zdroj: | Journal of Human Genetics |
| ISSN: | 1435-232X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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