RESUMEN
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.
Asunto(s)
Cilios/metabolismo , Predisposición Genética a la Enfermedad , Malformaciones del Desarrollo Cortical/diagnóstico , Malformaciones del Desarrollo Cortical/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación Missense , Fenotipo , Alelos , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Consanguinidad , Análisis Mutacional de ADN , Fibroblastos/metabolismo , Estudios de Asociación Genética/métodos , Homocigoto , Humanos , Masculino , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Moleculares , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/genética , Linaje , Conformación Proteica , Relación Estructura-Actividad , Secuenciación del ExomaRESUMEN
This article is a collaborative effort of five nurses who have worked together for a total of 173 collective years. We have experienced vast changes in the field of neonatology during the last 40 years and wish to share some of the significant developments as we experienced them in our unit. We realize that the various changes differ by location and institution.