Universität zu Köln

Ufartes, Roser, Berger, Hanna, Till, Katharina, Salinas, Gabriela, Sturm, Marc ORCID: 0000-0002-6552-8362, Altmueller, Janine, Nuernberg, Peter, Thiele, Holger ORCID: 0000-0002-0169-998X, Funke, Rudolf, Apeshiotis, Neophytos, Langen, Hendrik, Wollnik, Bernd, Borchers, Annette and Pauli, Silke (2020). De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome. Hum. Genet., 139 (11). S. 1363 - 1380. NEW YORK: SPRINGER. ISSN 1432-1203

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ufartes, Roser UNSPECIFIED UNSPECIFIED UNSPECIFIED Berger, Hanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Till, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Salinas, Gabriela UNSPECIFIED UNSPECIFIED UNSPECIFIED Sturm, Marc UNSPECIFIED orcid.org/0000-0002-6552-8362 UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED orcid.org/0000-0002-0169-998X UNSPECIFIED Funke, Rudolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Apeshiotis, Neophytos UNSPECIFIED UNSPECIFIED UNSPECIFIED Langen, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Borchers, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Pauli, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-333567
DOI:	10.1007/s00439-020-02175-x
Journal or Publication Title:	Hum. Genet.
Volume:	139
Number:	11
Page Range:	S. 1363 - 1380
Date:	2020
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POLYCOMB; AUTS2; MECHANISMS; PROTEINS; DELETION; MLL2 Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33356