De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome
| Autor: | Gabriela Salinas, Silke Pauli, Holger Thiele, Janine Altmüller, Katharina Till, Roser Ufartes, Hanna Berger, Hendrik Langen, Neophytos Apeshiotis, Marc Sturm, Rudolf Funke, Peter Nürnberg, Annette Borchers, Bernd Wollnik |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Gene isoform Microcephaly Adolescent Xenopus medicine.disease_cause 03 medical and health sciences Exon 0302 clinical medicine Intellectual Disability Genetics medicine Animals Humans Protein Isoforms Abnormalities Multiple Global developmental delay Child Genetics (clinical) Cellular localization Original Investigation 030304 developmental biology Lymphokines 0303 health sciences Mutation biology Exons Syndrome biology.organism_classification medicine.disease Phenotype Technology Platforms 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | Human Genetics |
| Popis: | We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome. |
| Databáze: | OpenAIRE |
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