Journal Article

De novo missense variants in FBXW11 cause diverse developmental phenotypes including brain, eye and digit anomalies


The identification of genetic variants implicated in human developmental disorders has been revolutionized by second-generation sequencing combined with international pooling of cases. Here, we describe seven individuals who have diverse yet overlapping developmental anomalies, and who all have de novo missense FBXW11 variants identified by whole exome or whole genome sequencing and not reported in the gnomAD database. Their phenotypes include striking neurodevelopmental, digital, jaw, and eye anomalies, and in one individual, features resembling Noonan syndrome, a condition caused by dysregulated RAS signaling. FBXW11 encodes an F-box protein, part of the Skp1-cullin-F-box (SCF) ubiquitin ligase complex, involved in ubiquitination and proteasomal degradation and thus fundamental to many protein regulatory processes. FBXW11 targets include b-catenin and GLI transcription factors, key mediators of Wnt and Hh signaling, respectively, critical to digital, neurological, and eye development. Structural analyses indicate affected residues cluster at the surface of the loops of the substrate-binding domain of FBXW11, and the variants are predicted to destabilize the protein and/or its interactions. In situ hybridization studies on human and zebrafish embryonic tissues demonstrate FBXW11 is expressed in the developing eye, brain, mandibular processes, and limb buds or pectoral fins. Knockdown of the zebrafish FBXW11 orthologs fbxw11a and fbxw11b resulted in embryos with smaller, misshapen, and underdeveloped eyes and abnormal jaw and pectoral fin development. Our findings support the role of FBXW11 in multiple developmental processes, including those involving the brain, eye, digits, and jaw.

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Holt, Richard J.
Young, Rodrigo M.
Crespo, Berta
Ceroni, Fabiola
Curry, Cynthia J.
Bellacchio, Emanuele
Bax, Dorine A.
Ciolfi, Andrea
Simon, Marleen
Fagerberg, Christina R.
van Binsbergen, Ellen
De Luca, Alessandro
Memo, Luigi
Dobyns, William B.
Mohammed, Alaa Afif
Clokie, Samuel J.H.
Zazo Seco, Celia
Jiang Yong-Hui
Sørensen, Kristina P.
Andersen, Helle
Sullivan, Jennifer
Powis, Zoë
Chassevent, Anna
Smith-Hicks, Constance
Petrovski, Slavé
Antoniadi, Thalia
Shashi, Vandana
Gelb, Bruce D.
Wilson, Stephen W.
Gerrelli, Dianne
Tartaglia, Marco
Chassaing, Nicolas
Calvas, Patrick
Ragge, Nicola K.

Oxford Brookes departments

Department of Biological and Medical Sciences


Year of publication: 2019
Date of RADAR deposit: 2019-07-31

Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License

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